Nasal delivery device

ABSTRACT

A drinking actuated device for delivering a substance to the nasal cavity of a subject, comprising:
         a container for containing the substance;   a nosepiece extending from the device for placement in proximity to the nose of a subject, with the nosepiece in fluid communication with the container;   a valve mechanically connectable to the container, characterized by an active configuration and an inactive configuration; and   a trigger mechanism adapted to reversibly reconfigure the valve from the active configuration to the inactive configuration. The mouthpiece is fluidly connectable to by means of a tubule to a fluid reservoir containing a fluid. Drawing liquid from the reservoir into the mouth via the mouthpiece reconfigures the valve from the inactive configuration to the active configuration for a predetermined period of time in response to the pressure gradient generated by the suction applied by the subject to the tubule.

FIELD OF THE INVENTION

The present invention generally relates to a nasal substance deliverydevice, and more specifically, to a drinking/breathing-actuated devicefor delivering a substance to a nasal cavity of a subject in a varietyof different delivery methods.

BACKGROUND OF THE INVENTION

Nasal delivery of a substance (e.g., a drug, a vaccine, etc.) can beuseful both for treating diseases or disorders of the nasal passagewaysthemselves and for treating other disorders or conditions through thesystemic route (e.g., vaccine, neurological, etc.). The advantages ofnasal delivery of a substance are, among others, the following:

(a) a rich vascular plexus—a direct route into the blood stream; (b)avoiding gastrointestinal destruction as drug degradation which isobserved in the gastrointestinal tract is absent. (c) Hepatic first passmetabolism (destruction of drugs by liver enzymes) is absent; (d) ratesof absorption and plasma concentrations are comparable to intravenousadministration; (e) ease, convenience and safety; (f) rapidlyachievement of therapeutic brain and spinal cord (CNS) drugconcentrations; (g) rapid drug absorption and quick onset of action canbe achieved; (h) the bioavailability of larger drug molecules can beimproved by means of absorption enhancers or other approaches; (i) Thenasal bioavailability for smaller drug molecules is good; (j) drugs thatare orally not absorbed can be delivered to the systemic circulation bynasal drug delivery; (k) based on published information, the nasal routewas indicated as an alternate to parenteral route, especially forprotein and peptide drugs; (l) convenient for the patients, especiallyfor those on long term therapy, when compared with parenteralmedication.

On the other hand, the limitations of nasal delivery of a substance are:

(a) the histological toxicity of absorption enhancers used in nasal drugdelivery system is not yet clearly established; (b) relativelyinconvenient to patients when compared to oral delivery systems sincethere is a possibility of nasal irritation; (c) nasal cavity providessmaller absorption surface area when compared to (Gastro intestinaltract GIT).

Therapy through intranasal administration has been an accepted form oftreatment in many countries. In recent years many drugs have been shownto achieve better systemic bioavailability through nasal route than byoral administration. Advances in biotechnology have made available alarge number of protein and peptide drugs for the treatment of a varietyof diseases. These drugs are unsuitable for oral administration becausethey are significantly degraded in the gastrointestinal tract orconsiderably metabolized by first pass effect in the liver. Also, theparenteral route is inconvenient for long term therapy. Of manyalternate routes tried, intranasal drug delivery is found much promisingfor administration of such drugs.

There are many traditional devices that are adapted to supply substancesto the nasal cavity. These devices include, for example, syringed nosedrops, pump spray devices, and fluorinated propellant metered doseinhalers (MDI). These traditional devices have not generally been ableto achieve the particle sizes necessary to maximize efficacy whilehelping mitigate undesired pulmonary absorption. For example, both eyedropper type devices and simple spray devices typically presentmedicament into the nasal cavity in a stream. The result is that much ofthe medicament simply runs out of the patient's nose, and only a smallamount of the drug is absorbed, with even less of the drug reaching thenasal epithelia.

In the recent years a few companies have developed novel drug deliverydevices which are activated when a subject exhales air from the lungsthrough the mouth. As a result of the air exhale, the soft palate isclosed, and thereby operates to isolate the nasal passageways from theremainder of the pulmonary system. By that, the soft palate acts as anatural check valve preventing the flow of air between the lungs and thenasal cavity. Thus, in these air-exhale based devices, it is believedthat nasal substance delivery can be improved if the patient is exhalingorally while the substance is being sprayed into the nasal passages. Onenasal delivery device that takes advantage of this phenomenon is shownin U.S. Pat. No. 6,715,485 to Optinose. This patent applicationdiscloses a delivery device for delivering a substance to the nasalairway of a subject, in particular the posterior region of the nasalairway, the delivery device comprising: a closure unit for causing theclosure of the oropharyngeal velum of the subject, and a delivery unitfor delivering a gas flow entraining a substance to one of the nostrilsof the subject at such a driving pressure as to flow around theposterior margin of the nasal septum and out of the other nostril of thesubject, wherein the delivery unit comprises a nosepiece which includesan outlet through which the gas flow in use is delivered to the onenostril and a sealing member for sealing the one nostril to the outletsuch as in use to prevent the escape of the gas flow through the onenostril.

The present invention takes advantage of the normal swallowing mechanismin which the soft palate closes, in the delivery process of a substanceto nose. In this mechanism the isolation of the nose passageways fromthe respiratory system is better than in the case of air exhalation (onwhich the nasal drug delivery devices known in the prior art is based).Furthermore, the present invention is able to deliver a desired amountof substance to the nasal epithelium while preventing entry into thepulmonary tract and the lungs. This substance delivery device has tocomply with the following key requirements: a. they have to be accuratein the doses of the substance they provide, b. good penetration to thenasal canals, c. painless, d. with minimal stomach deposition, e. withminimal lung deposition, f. easy to use, g. with improved patientcompliance, h. washing of the drug flavor, i. suitable platform forvarious drugs and vaccines, j. and with subject-independent actuation.The present invention is intended to comply with all these requirements.

SUMMARY OF THE INVENTION

It is one object of the present invention to provide an air-intakeactuated device adapted for delivering a substance to a nasal cavity ofa subject, said device comprising:

-   -   a. a container for containing said substance;    -   b. a nosepiece extending from said device for placement in        proximity to a nose of said subject, said nosepiece being in        fluid communication with said container;    -   c. a valve mechanically connectable to said container,        characterized by at least two configurations: (i) an active        configuration in which said valve enables delivery of        predetermined amount of said substance from said container to        said nasal cavity via said nosepiece; and, (ii) an active        configuration, in which said valve prevents delivery of said        predetermined amount of said substance from said container to        said nasal cavity;    -   d. a mouthpiece extending from said device for placement in a        mouth of said subject; and,    -   e. a trigger mechanism adapted to reconfigure said valve from        said active configuration to said inactive configuration, and        vice versa;    -   wherein said trigger mechanism is activated by means of said        subject intaking air through said mouthpiece;    -   further wherein said trigger mechanism is adapted to reconfigure        said valve from said inactive configuration to said active        configuration for a predetermined period of time in response to        said subject intake of air.

It is another object of the present invention to provide the air-intakeactuated device as defined above, wherein said trigger mechanism isadapted to reconfigure said valve from said active configuration to saidinactive configuration when said subject ceases said intake.

It is another object of the present invention to provide the air-intakeactuated device as defined above, additionally comprising anintermediate compartment adapted to be filled with predetermined amountof said substance; such that said delivery of said substance to saidsubject is from said intermediate compartment.

It is another object of the present invention to provide the air-intakeactuated device as defined above, wherein the operation of said triggermechanism is synchronized with said intake of air by said subject.

It is another object of the present invention to provide the air-intakeactuated device as defined above, wherein said trigger mechanismcomprises a pulsation mechanism adapted to reconfigure said valve fromsaid inactive configuration to said active configuration and vice versain sequence of pulses, each of which is characterized by a predeterminedlength of pulse, said valve adapted to a release said predeterminedamount of said substance according to said sequence of pulses.

It is another object of the present invention to provide the air-intakeactuated device as defined above, wherein in each said pulse at leasttwo doses of said predetermined amount of said substance are released.

It is another object of the present invention to provide the air-intakeactuated device as defined above, wherein said nosepiece is in fluidcommunication with said valve by means of a spray nozzle.

It is another object of the present invention to provide the air-intakeactuated device as defined above, wherein said spray nozzle ischaracterized by a diameter which influences on said predeterminedperiod of time.

It is another object of the present invention to provide the air-intakeactuated device as defined above, further comprising a cap adapted tocover at least a portion of the components of said device forsterilization/aseptic purposes.

It is another object of the present invention to provide the air-intakeactuated device as defined above, wherein said cap comprises an opening.

It is another object of the present invention to provide the air-intakeactuated device as defined above, wherein said container adapted to beconnected to an external container, said external container adapted tofill said container with said substance.

It is another object of the present invention to provide the air-intakeactuated device as defined above, wherein said external containeradapted to fill said container with a predetermined dose of saidsubstance.

It is another object of the present invention to provide the air-intakeactuated device as defined above, further comprising indicating meansadapted to indicate the amount of said substance within said container.

It is another object of the present invention to provide the air-intakeactuated device as defined above, wherein said indicating means is atransparent window located on a side of said container.

It is another object of the present invention to provide the air-intakeactuated device as defined above, wherein said substance is a drugselected from a group consisting of: Anti-Angiogenesis agents,Antisense, anti-ulcer, butorphanol, Calcitonin and analogs, COX-IIinhibitors, desmopressin and analogs, dihydroergotamine, Dopamineagonists and antagonists, Enkephalins and other opioid peptides, Growthhormone and analogs, growth hormone releasing hormone, Growth hormoneantagonists, immunoglobulin E (IgE) suppressors, Insulin, insulinotropinand analogs, Ketamine, Kytril (granisetron), Leutenizing hormonereleasing hormone and analogs, lidocaine, metoclopramide, Midazolam,Narcotic analgesics, neuraminidase inhibitors, nicotine, Non-steroidanti-inflammatory agents, Oligosaccharides, ondansetron, Parathyroidhormone and analogs, Parathyroid hormone antagonists, Prostaglandinantagonists, Prostaglandins, Recombinant soluble receptors, scopolamine,Serotonin agonists and antagonists, Sildenafil, Terbutaline,vasopressin, or any combination thereof.

It is another object of the present invention to provide the air-intakeactuated device as defined above, wherein said substance is a vaccinewith or without carriers and/or adjuvant selected from the groupconsisting of: Prophylactics and therapeutic antigens, subunit protein,peptide and polysaccharide, polysaccharide conjugates, toxoids, geneticbased vaccines, live attenuated, reassortant, inactivated, whole cells,viral and bacterial vectors for the treatment of arthritis,Lactobacillus species: Lactobacillus acetotolerans, Lactobacillusacidifarinae, Lactobacillus acidipiscis, Lactobacillus acidophilus(Doderlein bacillus), Lactobacillus agilis, Lactobacillus algidus,Lactobacillus alimentarius, Lactobacillus amylolyticus, Lactobacillusamylophilus, Lactobacillus amylotrophicus, Lactobacillus amylovorus,Lactobacillus animalis, Lactobacillus antri, Lactobacillus apodemi,Lactobacillus aviarius, Lactobacillus bifermentans, Lactobacillusbrevis, Lactobacillus buchneri, Lactobacillus camelliae, Lactobacilluscasei, Lactobacillus catenaformis, Lactobacillus ceti, Lactobacilluscoleohominis, Lactobacillus collinoides, Lactobacillus composti,Lactobacillus concavus, Lactobacillus coryniformis, Lactobacilluscrispatus, Lactobacillus crustorum, Lactobacillus curvatus,Lactobacillus delbrueckii, Lactobacillus delbrueckii subsp. Bulgaricus,Lactobacillus delbrueckii subsp. Lactis, Lactobacillus diolivorans,Lactobacillus equi, Lactobacillus equigenerosi, Lactobacillusfarraginis, Lactobacillus farciminis, Lactobacillus fermentum,Lactobacillus fornicalis, Lactobacillus fructivorans, Lactobacillusfrumenti, Lactobacillus fuchuensis, Lactobacillus gallinarum,Lactobacillus gasseri, Lactobacillus gastricus, Lactobacillus ghanensis,Lactobacillus graminis, Lactobacillus hammesii, Lactobacillus hamsteri,Lactobacillus harbinensis, Lactobacillus hayakitensis, Lactobacillushelveticus, Lactobacillus hilgardii, Lactobacillus homohiochii,Lactobacillus iners, Lactobacillus ingluviei, Lactobacillusintestinalis, Lactobacillus jensenii, Lactobacillus johnsonii,Lactobacillus kalixensis, Lactobacillus kefiranofaciens, Lactobacilluskefiri, Lactobacillus kimchii, Lactobacillus kitasatonis, Lactobacilluskunkeei, Lactobacillus leichmannii, Lactobacillus lindneri,Lactobacillus malefermentans, Lactobacillus mali, Lactobacillusmanihotivorans, Lactobacillus mindensis, Lactobacillus mucosae,Lactobacillus murinus, Lactobacillus nagelii, Lactobacillus namurensis,Lactobacillus nantensis, Lactobacillus oligofermentans, Lactobacillusoris, Lactobacillus panis, Lactobacillus pantheris, Lactobacillusparabrevis, Lactobacillus parabuchneri, Lactobacillus paracollinoides,Lactobacillus parafarraginis, Lactobacillus parakefiri, Lactobacillusparalimentarius, Lactobacillus paraplantarum, Lactobacillus pentosus,Lactobacillus perolens, Lactobacillus plantarum, Lactobacillus pontis,Lactobacillus psittaci, Lactobacillus rennini, Lactobacillus reuteri,Lactobacillus rhamnosus, Lactobacillus rimae, Lactobacillus rogosae,Lactobacillus rossiae, Lactobacillus ruminis, Lactobacillus saerimneri,Lactobacillus sakei, Lactobacillus salivarius, Lactobacillussanfranciscensis, Lactobacillus satsumensis, Lactobacillus secaliphilus,Lactobacillus sharpeae, Lactobacillus siliginis, Lactobacillus spicheri,Lactobacillus suebicus, Lactobacillus thailandensis, Lactobacillusultunensis, Lactobacillus vaccinostercus, Lactobacillus vaginalis,Lactobacillus versmoldensis, Lactobacillus vini, Lactobacillusvitulinus, Lactobacillus zeae, Lactobacillus zymae, Probiotics selectedfrom a group consisting of Lactic acid bacteria (LAB) andbifidobacteria, or any combination thereof; said substance is used forthe treatment of at least one selected from a group consisting ofcholera, moraxella catarrhali, cocaine addiction, Haemophilus influenzaetype b (Hib), meningococcus, measles, mumps, rubella, varicella, yellowfever, Respiratory syncytial virus, pneumococcus, streptococcus,typhoid, influenza, hepatitis, including hepatitis A, B, C and F, polio,human immunodeficiency virus (HIV), parainfluenza, rotavirus,cytomegalovirus (CMV), chlamydia, non-typeable haemophilus, moraxellacatarrhalis, human papilloma virus, tuberculosis including BacillusCalmette-Guerin (BCG), gonorrhoea, asthma, atheroschlerosis, malaria,otitis media, E-coli, Alzheimer's disease, H. Pylori, salmonella,diabetes, cancer, herpes simplex, Staphylococcus aureus, Streptococcus,or any combination thereof.

It is another object of the present invention to provide the air-intakeactuated device as defined above, wherein said substance is used for thetreatment of at least one selected from a group consisting of cholera,moraxella catarrhali, cocaine addiction, Hib, meningococcus, measles,mumps, rubella, varicella, yellow fever, Respiratory syncytial virus,pneumococcus, streptococcus, typhoid, influenza, hepatitis, includinghepatitis A, B, C and F, polio, HIV, parainfluenza, rotavirus, CMV,chlamydia, non-typeable haemophilus, moraxella catarrhalis, humanpapilloma virus, tuberculosis including BCG, gonorrhoea, asthma,atheroschlerosis, malaria, otitis media, E-coli, Alzheimer's disease, H.Pylori, salmonella, diabetes, cancer, herpes simplex, Staphylococcusaureus, Streptococcus, or any combination thereof.

It is another object of the present invention to provide the air-intakeactuated device as defined above, wherein the substance is a peptide orprotein therapeutic agent such as cytokines, hormones, clotting factors,vaccines, monoclonal antibody.

It is another object of the present invention to provide the air-intakeactuated device as defined above, used for the treatment of centralnervous system (CNS) disorders, brain disorders such as: brain cancer,acute brain injury, spinal cord injury, Alzheimer's disease,Neurogenesis, Parkinson's disease, depression, Epilepsy, schizophreniaby the delivery of substances such as: Neurotrophins, brain-derivedneurotrophic factor (BDNF), glial cell-derived neurotrophic factor(GDNF), anti-epidermal growth factor receptor antibodies (anti EGFreceptor AB), Enzymes such as Lysosomal enzyme, Neuregulin.

It is another object of the present invention to provide the air-intakeactuated device as defined above, wherein said substance is atherapeutic substance selected from a group consisting of: agents forthe common cold, Anti-addiction, anti-infectives, analgesics,anesthetics, anorexics, antiarthritics, anti-allergy agents,antiasthmatic agents, anticonvulsants, anti-depressants, antidiabeticagents, anti-depressants, anti-diuretics, anti-emetics, antihistamines,anti-inflammatory agents, antimigraine preparations, antimotion sicknesspreparations, antinauseants, antineoplastics, anti-obesity,antiosteoporeteic, antiparkinsonism drugs, antipruritics,antipsychotics, antipyretics, anticholinergics, benzodiazepineantagonists, bone stimulating agents, central nervous system stimulants,hormones, hypnotics, immunosuppressives, prostaglandins, proteins,peptides, polypeptides and other macromolecules, psychostimulants,rhinitis treatment, sedatives, sexual hypofunction, tranquilizers andvitamins including B12, probiotics, natural oils, natural ingredients,or any combination thereof.

It is another object of the present invention to provide the air-intakeactuated device as defined above, wherein said substance may bedelivered to said nasal cavity in a form selected from the groupconsisting of: a powder; a granule; a cachet; a capsule; a paste; acream; a gel; an ointment; a salve; a foam; a paste; a lotion; a cream;an oil suspension; a spray; a suspension; a solution; an emulsion; apatch; a stick; a spray, preferably a nasal spray, or a buccal spray; amouth wash, an aerosol, from a Venturi effect, and a drink.

It is another object of the present invention to provide the air-intakeactuated device as defined above, wherein said substance is selectedfrom a group consisting of natural oils; Mint oils, Peppermint oil,Spearmint oil, Menthol, Olive oil, Eucalyptus oil, Amino acids, fattyacids and any combination thereof.

It is another object of the present invention to a method for deliveringa substance to a nasal cavity of a subject, said method comprising stepsof:

-   -   a. providing an air-intake actuated device adapted for        delivering a substance to a nasal cavity of a subject, said        device comprising: (i) a container for containing said        substance; (ii) a nosepiece extending from said device for        placement in proximity to a nose of said subject, said nosepiece        being in fluid communication with said container; (iii) a valve        mechanically connectable to said container, characterized by at        least two configurations: (i) an active configuration in which        said valve enables delivery of predetermined amount of said        substance from said container to said nasal cavity via said        nosepiece; and, (ii) an inactive configuration, in which said        valve prevents delivery of said predetermined amount of said        substance from said container to said nasal cavity; (iv) a        mouthpiece extending from said device for placement in a mouth        of said subject; and, a (v) trigger mechanism adapted to        reconfigure said valve from said active configuration to said        inactive configuration, and vice versa; wherein said trigger        mechanism is activated by means of said subject intaking air        through said mouthpiece; further wherein said trigger mechanism        is adapted to reconfigure said valve from said inactive        configuration to said active configuration for a predetermined        period of time in response to said subject intake of air;    -   b. placing said nosepiece in or around the nose of said subject;    -   c. placing said mouthpiece in the mouth of said subject;    -   d. inhaling air; thereby reconfiguring said valve from said        inactive configuration to said active configuration for a        predetermined period of time in response;    -   e. releasing a predetermined amount of said substance from said        container to said nosepiece.

It is another object of the present invention to provide the method asdefined above, further comprising step of reconfiguring said valve viasaid trigger mechanism from said active configuration to said inactiveconfiguration when said subject ceases said intake.

It is another object of the present invention to provide the method asdefined above, additionally comprising step of providing said triggermechanism with a flexible membrane; said membrane is in mechanicalcommunication with said valve; such that when said subject intake air,said membrane is relocated from its initial position and said valve isopened.

It is another object of the present invention to provide the method asdefined above, additionally comprising step of providing said devicewith an intermediate compartment adapted to be filled with predeterminedamount of said substance; such that said delivery of said substance tosaid subject is from said intermediate compartment.

It is another object of the present invention to provide the method asdefined above, further comprising step of synchronizing the operation ofsaid trigger mechanism with said drinking of said fluid by said subject.

It is another object of the present invention to provide the method asdefined above, further comprising step of providing said triggermechanism with a pulsation mechanism adapted to reconfigure said valvefrom said inactive configuration to said active configuration and viceversa in sequence of pulses, each of which is characterized by apredetermined length of pulse, said valve adapted to a release saidpredetermined amount of said substance according to said sequence ofpulses.

It is another object of the present invention to provide the method asdefined above, further comprising step of releasing in each said pulseat least two doses of said predetermined amount of said substance.

It is another object of the present invention to provide the method asdefined above, wherein said nosepiece is in fluid communication withsaid valve by means of a spray nozzle.

It is another object of the present invention to provide the method asdefined above, wherein said spray nozzle is characterized by a diameterwhich influences on said predetermined period of time.

It is another object of the present invention to provide the method asdefined above, further comprising step of providing said device with acap adapted to cover at least a portion of the components of said devicefor sterilization/aseptic purposes.

It is another object of the present invention to provide the method asdefined above, wherein said cap comprises an opening.

It is another object of the present invention to provide the method asdefined above, wherein said container adapted to be connected to anexternal container, said external container adapted to fill saidcontainer with said substance.

It is another object of the present invention to provide the method asdefined above, further comprising step of filling said container by saidexternal container with a predetermined dose of said substance.

It is another object of the present invention to provide the method asdefined above, further comprising step of providing said container withindicating means adapted to indicate the amount of said substance withinsaid container.

It is another object of the present invention to provide the method asdefined above, wherein said indicating means is a transparent windowlocated on a side of said container.

It is another object of the present invention to provide the method asdefined above, wherein said substance is a drug selected from a groupconsisting of: Anti-Angiogenesis agents, Antisense, anti-ulcer,butorphanol, Calcitonin and analogs, COX-II inhibitors, desmopressin andanalogs, dihydroergotamine, Dopamine agonists and antagonists,Enkephalins and other opioid peptides, Growth hormone and analogs,growth hormone releasing hormone, Growth hormone antagonists, IgEsuppressors, Insulin, insulinotropin and analogs, Ketamine, Kytril(granisetron), Leutenizing hormone releasing hormone and analogs,lidocaine, metoclopramide, Midazolam, Narcotic analgesics, neuraminidaseinhibitors, nicotine, Non-steroid anti-inflammatory agents,Oligosaccharides, ondansetron, Parathyroid hormone and analogs,Parathyroid hormone antagonists, Prostaglandin antagonists,Prostaglandins, Recombinant soluble receptors, scopolamine, Serotoninagonists and antagonists, Sildenafil, Terbutaline, vasopressin, or anycombination thereof.

It is another object of the present invention to provide the method asdefined above, additionally comprising step of selecting said substancefrom a vaccine with or without carriers and/or adjuvant selected fromthe group consisting of: Prophylactics and therapeutic antigens, subunitprotein, peptide and polysaccharide, polysaccharide conjugates, toxoids,genetic based vaccines, live attenuated, reassortant, inactivated, wholecells, viral and bacterial vectors for the treatment of arthritis,Lactobacillus species: Lactobacillus acetotolerans, Lactobacillusacidifarinae, Lactobacillus acidipiscis, Lactobacillus acidophilus(Doderlein bacillus), Lactobacillus agilis, Lactobacillus algidus,Lactobacillus alimentarius, Lactobacillus amylolyticus, Lactobacillusamylophilus, Lactobacillus amylotrophicus, Lactobacillus amylovorus,Lactobacillus animalis, Lactobacillus antri, Lactobacillus apodemi,Lactobacillus aviarius, Lactobacillus bifermentans, Lactobacillusbrevis, Lactobacillus buchneri, Lactobacillus camelliae, Lactobacilluscasei, Lactobacillus catenaformis, Lactobacillus ceti, Lactobacilluscoleohominis, Lactobacillus collinoides, Lactobacillus composti,Lactobacillus concavus, Lactobacillus coryniformis, Lactobacilluscrispatus, Lactobacillus crustorum, Lactobacillus curvatus,Lactobacillus delbrueckii, Lactobacillus delbrueckii subsp. Bulgaricus,Lactobacillus delbrueckii subsp. Lactis, Lactobacillus diolivorans,Lactobacillus equi, Lactobacillus equigenerosi, Lactobacillusfarraginis, Lactobacillus farciminis, Lactobacillus fermentum,Lactobacillus fornicalis, Lactobacillus fructivorans, Lactobacillusfrumenti, Lactobacillus fuchuensis, Lactobacillus gallinarum,Lactobacillus gasseri, Lactobacillus gastricus, Lactobacillus ghanensis,Lactobacillus graminis, Lactobacillus hammesii, Lactobacillus hamsteri,Lactobacillus harbinensis, Lactobacillus hayakitensis, Lactobacillushelveticus, Lactobacillus hilgardii, Lactobacillus homohiochii,Lactobacillus iners, Lactobacillus ingluviei, Lactobacillusintestinalis, Lactobacillus jensenii, Lactobacillus johnsonii,Lactobacillus kalixensis, Lactobacillus kefiranofaciens, Lactobacilluskefiri, Lactobacillus kimchii, Lactobacillus kitasatonis, Lactobacilluskunkeei, Lactobacillus leichmannii, Lactobacillus lindneri,Lactobacillus malefermentans, Lactobacillus mali, Lactobacillusmanihotivorans, Lactobacillus mindensis, Lactobacillus mucosae,Lactobacillus murinus, Lactobacillus nagelii, Lactobacillus namurensis,Lactobacillus nantensis, Lactobacillus oligofermentans, Lactobacillusoris, Lactobacillus panis, Lactobacillus pantheris, Lactobacillusparabrevis, Lactobacillus parabuchneri, Lactobacillus paracollinoides,Lactobacillus parafarraginis, Lactobacillus parakefiri, Lactobacillusparalimentarius, Lactobacillus paraplantarum, Lactobacillus pentosus,Lactobacillus perolens, Lactobacillus plantarum, Lactobacillus pontis,Lactobacillus psittaci, Lactobacillus rennini, Lactobacillus reuteri,Lactobacillus rhamnosus, Lactobacillus rimae, Lactobacillus rogosae,Lactobacillus rossiae, Lactobacillus ruminis, Lactobacillus saerimneri,Lactobacillus sakei, Lactobacillus salivarius, Lactobacillussanfranciscensis, Lactobacillus satsumensis, Lactobacillus secaliphilus,Lactobacillus sharpeae, Lactobacillus siliginis, Lactobacillus spicheri,Lactobacillus suebicus, Lactobacillus thailandensis, Lactobacillusultunensis, Lactobacillus vaccinostercus, Lactobacillus vaginalis,Lactobacillus versmoldensis, Lactobacillus vini, Lactobacillusvitulinus, Lactobacillus zeae, Lactobacillus zymae, Probiotics selectedfrom a group consisting of Lactic acid bacteria (LAB) andbifidobacteria, or any combination thereof; said substance is used forthe treatment of at least one selected from a group consisting ofcholera, moraxella catarrhali, cocaine addiction, Hib, meningococcus,measles, mumps, rubella, varicella, yellow fever, Respiratory syncytialvirus, pneumococcus, streptococcus, typhoid, influenza, hepatitis,including hepatitis A, B, C and F, polio, HIV, parainfluenza, rotavirus,CMV, chlamydia, non-typeable haemophilus, moraxella catarrhalis, humanpapilloma virus, tuberculosis including BCG, gonorrhoea, asthma,atheroschlerosis, malaria, otitis media, E-coli, Alzheimer's disease, H.Pylori, salmonella, diabetes, cancer, herpes simplex, Staphylococcusaureus, Streptococcus, or any combination thereof.

It is another object of the present invention to provide the method asdefined above, wherein said substance is used for the treatment of atleast one selected from a group consisting of cholera, moraxellacatarrhali, cocaine addiction, Hi meningococcus, measles, mumps,rubella, varicella, yellow fever, Respiratory syncytial virus,pneumococcus, streptococcus, typhoid, influenza, hepatitis, includinghepatitis A, B, C and F, polio, HIV, parainfluenza, rotavirus, CMV,chlamydia, non-typeable haemophilus, moraxella catarrhalis, humanpapilloma virus, tuberculosis including BCG, gonorrhoea, asthma,atheroschlerosis, malaria, otitis media, E-coli, Alzheimer's disease, H.Pylori, salmonella, diabetes, cancer herpes simplex, Staphylococcusaureus, Streptococcus, or any combination thereof.

It is another object of the present invention to provide the method asdefined above, wherein the substance is a peptide or protein therapeuticagent such as cytokines, hormones, clotting factors, vaccines,monoclonal antibody.

It is another object of the present invention to provide the method asdefined above, used for the treatment of CNS disorders, brain disorderssuch as: brain cancer, acute brain injury, spinal cord injury,Alzheimer's, disease, Neurogenesis, Parkinson's disease, depression,Epilepsy, schizophrenia by the delivery of substances such as:Neurotrophins, BDNF, GDNF, anti EGF receptor AB, Enzymes such asLysosomal enzyme, Neuregulin.

It is another object of the present invention to provide the method asdefined above, wherein said substance is a therapeutic substanceselected from a group consisting of: Agents for the common cold,Anti-addiction, anti-infectives, analgesics, anesthetics, anorexics,antiarthritics, anti-allergy agents, antiasthmatic agents,anticonvulsants, anti-depressants, antidiabetic agents,anti-depressants, anti-diuretics, anti-emetics, antihistamines,anti-inflammatory agents, antimigraine preparations, antimotion sicknesspreparations, antinauseants, antineoplastics, anti-obesity,antiosteoporeteic, antiparkinsonism drugs, antipruritics,antipsychotics, antipyretics, anticholinergics, benzodiazepineantagonists, bone stimulating agents, central nervous system stimulants,hormones, hypnotics, immunosuppressives, prostaglandins, proteins,peptides, polypeptides and other macromolecules, psychostimulants,rhinitis treatment, sedatives, sexual hypofunction, tranquilizers andvitamins including B12, probiotics, natural oils, natural ingredients,or any combination thereof.

It is another object of the present invention to provide the method asdefined above, wherein said substance is delivered to said nasal cavityin a form selected from the group consisting of: a powder, a granule; acachet; a capsule; a tablet; a paste; a cream; a gel; an ointment; asalve; a foam; a paste; a lotion; a cream; an oil suspension; a spray; asuspension; a solution; an emulsion; a patch; a stick; a spray,preferably a nasal spray, or a buccal spray; a mouth wash; an aerosol,from a Venturi effect; and a drink.

It is another object of the present invention to provide the method asdefined above, additionally comprising step of selecting said substancefrom a group consisting of natural oils; Mint oils, Peppermint oil,Spearmint oil, Menthol, Olive oil, Eucalyptus oil, Amino acids, fattyacids and any combination thereof.

BRIEF DESCRIPTION OF THE FIGURES

For a better understanding of the invention and to show how the same maybe carried into effect, reference will now be made, purely by way ofexample, to the accompanying drawings in which like numerals designatecorresponding elements or sections throughout. In the accompanyingdrawings:

FIG. 1 is an illustration of the pattern of breathing while drinkingaccording to a study of J. Smith et al.

FIGS. 2 a-c are an illustration of the pattern of swallowing andbreathing according to the study of J. Smith et al.

FIGS. 3 a-f are a schematic illustration of the motor events of theswallowing reflex;

FIGS. 4 a-h are a schematic illustration of the mechanism of adrinking-actuated substance delivery device of the present invention andthe swallowing mechanism of a subject;

FIG. 5 is a schematic illustration of the drinking-actuated substancedelivery device according to one embodiment of the present invention;

FIG. 6 is a schematic illustration of the a cross-section of thedrinking-actuated substance delivery device according to anotherembodiment of the present invention;

FIG. 7 is a schematic illustration of the a cross-section of thedrinking-actuated substance delivery device according to anotherembodiment of the present invention;

FIG. 8 is a schematic side-view illustration of the drinking-actuatedsubstance delivery device according to another embodiment of the presentinvention;

FIG. 9 is a schematic illustration of the controlling member accordingto one embodiment of the present invention;

FIG. 10 is a schematic illustration of the specific elements of thedrinking-actuated substance delivery device according to anotherembodiment of the present invention;

FIG. 11 is a schematic illustration of the drinking-actuated substancedelivery device according to another embodiment of the presentinvention;

FIG. 12 illustrates another embodiment of the present invention in whichan inhaling-actuating device 500 is presented.

FIGS. 13-14 illustrate the basic concept behind the idea.

FIGS. 15-19 b illustrates a first specific mechanism of theinhaling-actuating device 500.

FIGS. 18 a-18 b and 19 a-19 b provide a closer view of the actuationstep of device 500.

FIGS. 20-26 e illustrate a second embodiment 600 of the presentinvention.

FIGS. 27-28 illustrate another embodiment of the present invention.

FIGS. 29-38 illustrate a third mechanism 700 based on the intake of air.

FIGS. 38 a-38 b illustrate the top part 550 prior to and post loading ofthe medicament 560.

FIGS. 39-41 illustrate a fourth embodiment of the inhaling-actuatingdevice 800.

The drawings together with the description make apparent to thoseskilled in the art how the invention may be embodied in practice.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Before explaining at least one embodiment of the invention in detail, itis to be understood that the invention is not limited in its applicationto the details of construction and the arrangement of the components setforth in the following description or illustrated in the drawings. Theinvention is applicable to other embodiments or of being practiced orcarried out in various ways. Also, it is to be understood that thephraseology and terminology employed herein is for the purpose ofdescription and should not be regarded as limiting. The presentinvention discloses an intranasal substance delivery platform, givingsynchronized delivery of drug and improving patient's compliance byeliminating bad flavor and insuring dose delivery.

The term ‘substance’ refers hereinafter to any material which may beused for delivery to the nasal cavity of a subject for medical and alikepurposed. According to different embodiments of the present invention,the substance may be delivered to the nasal cavity in a form of apowder; a granule; a cachet; a capsule; a tablet; a paste; a cream; agel; an ointment; a salve; a foam; a paste; a lotion; a cream; an oilsuspension; a spray; a suspension; a emulsion; a patch; a stick; aspray; preferably a nasal spray, or a buccal spray; a mouth wash; anaerosol; from a Venturi effect; or a drink

The term ‘pressure gradient’ refers hereinafter to physical quantitythat describes in which direction and/or at what rate the pressurechanges the most rapidly around a particular location.

The term ‘suction’ refers hereinafter to the flow of a fluid (e.g., air,liquid) into a partial vacuum, or region of low pressure. The pressuregradient between this region and the ambient pressure will propel mattertoward the low pressure area.

The term ‘drinking’ in the current invention is associated with thephysiological process of swallowing in the human or animal body thatmakes something pass from the mouth, to the pharynx, into the esophagus,with the shutting of the epiglottis and closing the soft palate.According to the present invention, drinking is accompanied with suctionof a fluid through a tubule.

The term ‘nasal passageways’ refers hereinafter to the nasal passagewaysof a nose of a subject.

The term ‘release’ refers hereinafter to extraction of substance in amanner which can be, for example, spraying, sprinkling, scattering,dispersing, etc.

The term ‘predetermined amount of substance’ is a specific dose of asubstance that can be regulated by the device.

The term ‘coordination’ refers hereinafter to a synchronized order ofthe following: mastication, deglutition and respiration in which anaspiration is prevented.

According to the study of J. Smith et al. (Coordination of Eating,Drinking and Breathing in Adults, John Smith, et. al., Chest, 1989,96:33, 578-582), it was shown that swallowing occurred almostexclusively in expiration (in the study 271 patients were tested inwhich only two occurred in inspiration). This physiologic phenomenon isvery important for a proper operation of the device provided by thepresent invention.

According to one embodiment of the present invention, a substance isreleased into the nasal passageways of a subject and does not reach thepulmonary region (which can occur while inspiring). According to J.Smith et al's research, there is a full coordination between drinkingand breathing, such that when the subject is drinking a fluid, aninspiration is prevented, thus, at this stage, the substance can besafely released into the nasal passageways of the subject.

The present invention provides an air-intake actuated device adapted fordelivering a substance to a nasal cavity of a subject, said devicecomprising (a) a container for containing said substance; (b) anosepiece extending from said device for placement in proximity to anose of said subject, said nosepiece being in fluid communication withsaid container; (c) a valve mechanically connectable to said container,characterized by at least two configurations: (i) an activeconfiguration in which said valve enables delivery of predeterminedamount of said substance from said container to said nasal cavity viasaid nosepiece; and, (ii) an inactive configuration, in which said valveprevents delivery of said predetermined amount of said substance fromsaid container to said nasal cavity; (d) a mouthpiece extending fromsaid device for placement in a mouth of said subject; and, (e) a triggermechanism adapted to reconfigure said valve from said activeconfiguration to said inactive configuration, and vice versa; whereinsaid trigger mechanism is activated by means of said subject intakingair through said mouthpiece; further wherein said trigger mechanism isadapted to reconfigure said valve from said inactive configuration tosaid active configuration for a predetermined period of time in responseto said subject intake of air.

The present invention further provides a drinking-actuated deviceadapted for delivering a substance to a nasal cavity of a subject; thedevice comprising: (a) a container for containing said substance; (b) anosepiece extending from said device for placement in proximity to anose of said subject, said nosepiece being in fluid communication withsaid container; (c) a valve mechanically connectable to said container,characterized by at least two configurations: (i) an activeconfiguration in which said valve enables delivery of predeterminedamount of said substance from said container to said nasal cavity viasaid nosepiece; and, (ii) an inactive configuration; (d) a mouthpieceextending from said device for placement in a mouth of said subject;and, (e) a trigger mechanism adapted to reconfigure said valve from saidactive configuration to said inactive configuration, and vice versa;wherein said mouthpiece is fluidly connectable by means of a tubule to afluid reservoir containing a fluid, said fluid reservoir is adapted tosupply said fluid to said mouth of said subject via said mouthpiece;further wherein said trigger mechanism is adapted to reconfigure saidvalve from said inactive configuration to said active configuration fora predetermined period of time in response to a pressure gradientgenerated by suction applied by said subject to said tubule for drinkingsaid fluid through said tubule.

FIG. 1 illustrates the pattern of breathing while drinking according tothe study of J. Smith et al. The top graph illustrates tidal breathing,and the bottom graph illustrates the submental EMG (Electromyography),both related to the swallowing process. The arrows presented in thefigure indicate swallows. The figure demonstrates that during drinking(the bottom graph) there is no change in the breathing pattern (uppergraph). Hence it can be concluded that there is no breathing whiledrinking.

The different patterns of swallowing and breathing were also studied byJ. Smith et al., and are illustrated in FIGS. 2 a-2 c. As will bedemonstrated, the inspiration is terminated while swallowing occurs. Thetop graphs illustrate the change in volume during tidal breathing, andthe bottom graphs illustrate the submental EMG. In FIG. 2 a, the swallowoccurs at the beginning of expiration (end of inspiration). In themajority of swallows, as illustrated in FIG. 2 b, the swallows occurredin the midexpiration and followed by expiration. Occasionally, asillustrated in FIG. 2 c, the swallows occurred close to end expiration,and were usually followed by a further expiration. In each of the casesillustrated in FIGS. 2 a-2 c, the inspiration is terminated whileswallowing occurs.

FIGS. 3 a-3 f schematically illustrate the motor events of theswallowing reflex (e.g., while drinking), on which the device of thepresent invention is based on.

As was discussed above, there is ample evidence to suggest an importantrelationship between swallowing and breathing. Swallowing may beinitiated by stimulation of many sites in the upper respiratory tract,though most studies suggest the epiglottis and larynx are the mostsensitive areas for initiation of the swallowing reflex. FIG. 3 aillustrates the onset of the swallowing reflex when a subject 60swallows bolus 61 (e.g., water, food, etc.).

Said figure illustrates the tip of the tongue 62 in contact with theanterior part of the palate 63. The bolus 61 is pushed backward ingroove between the tongue 62 and the palate 63. As a result, the softpalate 64 is being drawn upward, such that the nasal passageways 65 andthe respiratory system 66 are isolated from each other.

As can be seen in FIG. 3 b, the bolus 61 has reached the vallecula, thehyoid bone and the larynx 67 move upward and forward, the epiglottis 68is tipped downward, and the contraction wave on posterior pharyngealwall moves downward. As can be seen in FIG. 3 c, the soft palate 64 hasbeen pulled down and has been approximated to the root of the tongue 62by contraction of the pharyngopalatine muscles, and by pressure of adescending pharyngeal contraction wave.

Following that, the cricopharyngeus muscle is opened to permit entry ofthe bolus into the esophagus 69, and the trickle of the bolus 61 entersalso the laryngeal opening 70 but is prevented from going further byclosure of the ventricular folds.

As can be seen in FIG. 3 d, the contraction wave has reached thevallecula and is pressing out the remains of the bolus 61. Now the bolushas largely passed through the upper sphincter into esophagus 69. As canbe seen in FIG. 3 e, the contraction wave has passed the pharynx, theepiglottis 68 is beginning to turn up again as hyoid bone and the larynxdescends. Now, the communication with the nasopharynx has beenre-established.

In FIG. 3 f, all structures of the pharynx have returned to restingposition.

As was disclosed above, the present invention takes advantage of thephysiological process illustrated in FIG. 3 a-3 f. When the soft palateis drawn upwardly and closes, a substance (e.g., a drug, a vaccine,etc.) can be delivered to the nasal passageways, without reaching therepository system and the lungs.

Reference is now made to FIG. 4 a-4 f which schematically illustrate themechanism of a drinking-actuated substance delivery device 10 of thepresent invention and the action of the swallowing mechanism of asubject 90 according to some embodiments of the invention.

According to FIG. 4 a, a nosepiece 11 of device 10 is inserted into thenose of subject 90, and mouthpiece 12 is inserted into said subject'smouth 18. According to said embodiments, device 10 is fluidly connectedto fluid reservoir 50 (e.g., a bottle, a can, etc.) such that subject 90drinks fluid 51 (e.g., water, a juice, a fluid medication, a cold fluid,a warm fluid etc.) through device 10. In FIG. 4 a, the soft palate 20 ofsubject 90 is opened, such that subject 90 is able to breath. FIG. 4 billustrates the activation of device 10. When subject 90 begins to drinkfluid 51, the swallowing reflex is activated, such that soft palate 20is closed.

Simultaneously to the passage of fluid 51 within the throat of saidsubject, a predetermined amount of substance 15 is delivered from device10 to nasal passageways 30 into the subject's nose.

As illustrated in FIG. 4 c, the subject had finished drinking said fluidand the substance 15 had been delivered to nasal passageways 30.

According to FIG. 4 d, said fluid has been swallowed by subject 90,substance 15 has been already diffused within nasal passageways 30 andthe soft palate is opened again.

According to FIG. 4 e, a nosepiece of the device 10 is inserted into thenose of subject 90, the mouthpiece is inserted into said subject'smouth, and the device is fluidly connected to the fluid reservoir (e.g.,a bottle, a can, etc.) such that subject 90 is able to drink the fluid(e.g., water, a juice, a fluid medication, a cold fluid, a warm fluidetc.) through the device. In FIG. 4 e, the soft palate 20 of subject 90is opened, such that subject 90 is able to breathe.

FIG. 4 f illustrates the activation of device 10. When subject 90 beginsto drink fluid 51, the swallowing reflex is activated, such that softpalate 20 is closed.

As illustrated in FIG. 4 g, the subject is drinking said fluid andsimultaneously a predetermined amount of substance 15 is delivered fromdevice 10 to nasal passageways 30 into the subject's nose.

According to FIG. 4 h, said fluid has been swallowed by the subject,substance 15 is in the process of diffusion within the nasal passagewaysand the soft palate is opened again.

FIG. 5 schematically illustrates one embodiment of the drinking-actuatedsubstance delivery device 200 for delivering a substance to a nasalcavity of a subject.

According to this figure, drinking-actuated device 200 comprises thefollowing main element:

-   a. A container 195 for containing said substance (not shown).-   b. A nosepiece 190 extending from drinking-actuated device 200 for    placement in proximity to a nose of said subject. Nosepiece 190 is    in fluid communication with container 195. The substance is adapted    to be administrated through nosepiece 190 to the nose of the    subject.-   c. A valve 145 mechanically connectable to container 195. Valve 145    is characterized by at least two configurations:    -   i. an active configuration in which valve enables the delivery        of predetermined amount of substance from container 195 to the        nasal cavity of the subject via nosepiece 190; and,    -   ii. an inactive configuration in which the substance is not        delivered to the nose of the subject.-   d. A mouthpiece 111 extending from device 200 for placement in a    mouth of the subject.

e. A trigger mechanism 120 adapted to reconfigure valve 145 from theactive configuration to the inactive configuration, and vice versa; and

-   f. A tubule 110 fluidly connectable with mouthpiece 111 and a fluid    reservoir 105 containing a fluid 107. Fluid reservoir 105 is adapted    to supply fluid 107 to the mouth of the subject via mouthpiece 111.

According to some embodiments of the present invention, the triggermechanism 120 which is adapted to reconfigure valve 145 from theinactive configuration to the active for a predetermined period of timein response to a pressure gradient generated by suction applied totubule 110 (through mouthpiece 111) while the subject sucks and drinksfluid 107 through tubule 110.

Trigger mechanism 120 is adapted to reconfigure valve 145 from theactive configuration to the inactive configuration when the pressuregradient is absent.

According to some embodiments, valve 145 is reconfigurable from theinactive configuration to the active configuration when the pressuregradient applied is above a predetermined threshold.

According to the present invention, while using device 200, thesubstance is delivered to the nose of the subject while the same drinksfluid 107.

During the drinking of the fluid 107, the swallowing reflex isactivated, and a result the soft palate of the subject is closed. Duringthis process, the nasal cavity of the subject is substantially isolatedfrom the remainder of the pulmonary system, so that the delivery of thesubstance to the nasal cavity may be performed safely.

According to some embodiments, the operation of nosepiece 90 and valve145 is similar to an operation known in the art as a spray device whichis able to generate a spray effect on the target tissue.

According to a specific embodiment of trigger mechanism 120 which isillustrated in FIG. 5, trigger mechanism 120 comprises a controllingmember 130 vertically positioned relatively to tubule 110.

Controlling member 130 has three main portions: a first end 126positioned within tubule 110; a middle portion 127 in communication witha membrane 140; and, a second end 128.

As will be explained hereinafter, when second end 128 is incommunication with valve 145, the valve is in the inactiveconfiguration; and, when second end 128 of the controlling member is notin communication with valve 145, the to the valve 145 is reconfigured tothe active configuration.

The connection of first end 126 of controlling member 130 and tubule 110is performed through an aperture 133. First end 126 is reciprocallymovable within tubule 110 and second end 128 is reciprocally movablewithin valve 145 in response to the pressure gradient.

Controlling member 130 has two configurations:

-   i. a closed configuration (illustrated in FIGS. 5 and 6) in which    fluid is not provided to the subject via tubule 110 and valve 145 is    in the inactive configuration; and,-   ii. an opened configuration (illustrated in FIG. 7) in which the    subject drinks fluid 107 through tubule 110 and valve 145 is in the    active configuration.

According to different embodiments of the present invention, controllingmember 130 may be positioned with respect to tubule 110 at anypredetermined angle between about 5° and about 175°.

According to different embodiments of the present invention and theembodiment of FIG. 5, trigger mechanism 120 comprises a pressureresponsive cavity 124 mechanically connected to controlling member 130in middle portion 127.

Cavity 124 is a pressure responsive cavity which is adapted toreconfigure controlling member 130 from the closed configuration to theopened configuration, and vice versa.

When a pressure gradient is applied (i.e., when the subject sucks ontubule 110 through mouthpiece 111), the controlling member isreconfigures to the opened configuration, and when the pressure gradientis absent, the controlling member is reconfigured to the closedconfiguration.

In the closed configuration, controlling member 130 is adapted to blockthe passage of fluid 107 from fluid reservoir 105 to 111 mouthpiecethrough tubule 110.

The reconfiguration of connecting member 130 between the twoconfigurations is performed via flexible membrane 140 which is anessential part of cavity 124.

Flexible membrane 140 is mechanically connected to connecting member 130by surrounding the same in middle portion 127.

Flexible membrane 140 is adapted to change its shape (e.g, to an archedshape) in response to the pressure gradient in tubule 110. As a resultof this shape change, controlling member 130 will be dragged towardstubule 110 and reconfigured from the closed configuration to the openedconfiguration.

Controlling member 130 comprises two apertures:

-   (i) a first aperture 133 which is adapted to fluidly communicate    between cavity 124 and mouthpiece 111 through at least a part of    tubule 110. First aperture 133 is extendable within controlling    member 130 from the area of tubule 110 to the area of cavity 124.    First aperture 133 is adapted to ‘transfer’ the pressure gradient    from said tubule 110 to cavity 124, such that controlling member 130    is reconfigured from the closed configuration to the opened    configuration.-   (ii) A second aperture 134 adapted to facilitate passage of fluid    107 through controlling member 130 when controlling member 130 is in    the opened configuration. Second aperture 134 is in fluid    communication with the upper part of first aperture 133. While being    in the opened configuration, the passage of fluid 107 within second    aperture 134 is adapted to preserve controlling member 130 in this    configuration as fluid 107 passes through controlling member 130.

According to the embodiment of FIG. 5, valve 145 comprises a spring 180which is at least partially tensed in the in configuration of the valve,and at least partially released in the active configuration of thevalve.

In the at least partially tensed position of spring 180, more staticenergy is stored within the spring relative to the at least partiallyreleased position of spring 180.

According to this embodiment, valve 145 further comprises a piston 170to which spring 180 is connected. Piston 170 is adapted to push viaspring 180 container 195 towards a needle 160. As result of this, thesubstance will be released to the patient through nosepiece 190.

In said inactive configuration, piston 170 is not pushing container 195.Furthermore, in said active configuration, in which spring 180 isreleased, the static energy stored within the spring is converted to apushing energy actuated on container 195 via piston 170.

The reconfiguration of the valve from the inactive configuration to theactive configuration is performed when second end 128 moved down as aresult of the reconfiguration of connecting element 130 from the closedconfiguration to the opened configuration.

According to other embodiments, valve 145 may comprise a spring which isat least partially released in the in active configuration, and at leastpartially tensed in the active configuration.

According to some embodiments, tubule 110 is at least partially a straw.According to other embodiments, the device of the present invention maybe connected to a straw which may be inserted within the fluidreservoir.

According to the embodiment of FIG. 5, the operation of triggermechanism 120 is synchronized with the drinking of fluid 107 byperformed by the subject

According to some embodiments, trigger mechanism 120 comprises apulsation mechanism adapted to reconfigure valve 145 from the inactiveconfiguration to the active configuration and vice versa in sequence ofpulses, each of which is characterized by a predetermined length ofpulse.

Valve 145 adapted to a release the predetermined amount of the substanceaccording to the sequence of pulses. For example, in each pulse at leasttwo doses of said predetermined amount of said substance are released.

According to some embodiments, nosepiece 190 may comprise a spray nozzle191. According to some embodiments, the spray nozzle may becharacterized by a diameter which influences said predetermined periodof time.

Reference is now made to FIG. 6 which schematically illustrates a crosssection of device 200. According to this figure, controlling member 130is in the closed configuration, and a result of that, valve 145 is inthe inactive configuration.

When a subject (not shown) drinks a fluid via tubule 110 and opening 113and mouthpiece 111, a pressure gradient is formed within said tubule.Such fluid may be stored within a fluid reservoir (not shown). Thepressure gradient which is formed within part of tubule 110 is deliveredalso to cavity 124 through first aperture 133.

Reference is now made to FIG. 7. According to this figure, as a resultof the pressure gradient which is formed within cavity 124, flexiblemembrane 140 is moved downwards. As a result of that, controlling member130 is dragged (by means of said membrane 140) to recess 138, and thusreconfigured from the closed configuration to the opened configuration.

In the opened configuration, the following two features occur:

1) The fluid flows within tubule 110 through first end 126 ofcontrolling member 130.

2) As a result of the movement of the controlling member 130 and hencethe second end 128 (e.g., a safety catch), the valve 145 is reconfiguredfrom the inactive active configuration to the active configuration. As aresult of that, the substance is delivered from container 195 to thenasal cavity of the patient via nosepiece (not shown).

According to some embodiments, the substance may is stored withincontainer 195 under a predetermined pressure. Therefore, when needle 160contacts a specific point in container 195, the substance may bereleased (e.g., as a spray).

According to some embodiments, valve 145 may comprise more than oneelement which reconfigures it to the active configuration.

According to other embodiments, container 195 is a syringe.

According to other embodiments, device 200 may further comprise a capwhich is adapted to cover at least a portion of the components of saiddevice for sterilization/aseptic purposes. This cap may comprise anopening.

According to some embodiments, container 195 is adapted to be connectedto an external container (not shown). The external container is adaptedto fill container 195 with a predetermined dose of a substance.

According to some embodiments, device 200 may further compriseindicating means adapted to indicate the amount of said substance withinsaid container. The indicating means may be a transparent window locatedon a side of the container.

According to some embodiments, fluid 107 may be selected from a groupconsisting of: water, a juice, a fluid medication, a cold fluid, a warmfluid, or any combination thereof.

Reference is now made to FIG. 8 which schematically illustrates aspecific embodiment of device 300 according to the present invention.

According to this figure, device 300 comprises a nosepiece 290, amouthpiece 211, a tubule 210, and a triggering mechanism 220.

According to this embodiment, the device 300 comprises a recess 238 towhich the controlling member (not shown) enters when it reconfiguredfrom the closed configuration to the opened configuration (so as toreconfigure the valve from the inactive configuration to the activeconfiguration).

The edge 212 of tubule 210 may be inserted into a fluid reservoir (notshown).

Reference is now made to a specific embodiment of controlling member130.

According to this embodiment, controlling member 130 has three mainportions: a first end 126; a middle portion 127; and, a second end 128.

The first end 126 is adapted to be placed within tubule 110. The middleportion 127 is adapted to be connected to membrane 140. The second end128 is adapted to be reversibly connected to valve 145.

First end 126 is reciprocally movable within tubule 110 and second end128 is reciprocally movable with respect to valve 145 in responsive tothe pressure gradient generated within tubule 110.

FIG. 9 provides a better view of the first aperture 133 and the secondaperture 134.

First aperture 133 is adapted to be in fluid communication with thecavity 124 and the mouthpiece 111 through a portion of tubule 110.

First aperture 133 extends within controlling member 130 from the areaof tubule 110 to the area of cavity 124. First aperture 133 is adaptedto transmit the pressure gradient from said tubule 110 to cavity 124(once the user sucks/drinks the fluid), such that controlling member 130is reconfigured from the closed configuration to the openedconfiguration.

Second aperture 134 is adapted to facilitate passage of fluid 107through controlling member 130 when controlling member 130 is in theopened configuration.

Second aperture 134 is in fluid communication with the upper part offirst aperture 133. While the controlling member 130 is in the openedconfiguration, the passage of fluid 107 thought second aperture 134 isadapted to preserve and maintain the controlling member 130 in theopened configuration.

FIG. 10 illustrates another embodiment of several parts of the deviceaccording to the present invention. In this figure the followingcomponents are illustrated: controlling member 130, tubule 110, andmouthpiece 111.

Reference is now made to FIG. 11 which schematically illustrates anotherembodiment of the drinking-actuated substance delivery device 400.

The drinking-actuated device 400 includes housing 310, having amouthpiece 320 which extends out from device 300.

Mouthpiece 320 is adapted to be placed in a mouth of a subject. Housing310 also contains container 330 which is adapted to contain substance332 (e.g., a drug, a vaccine, etc.).

Container 330 is in a fluid communication with nosepiece 340 throughvalve 335.

Nosepiece 340 extends from device 400, and is adapted to be placed in oraround a nose of a subject.

Valve 335 is adapted to regulate passage of substance 332 from container330 to nosepiece 340. The operation of valve 335 is performed by triggermechanism 337 which is adapted to transform valve 335 from an inactiveconfiguration to an active configuration, and vice versa.

According to the present invention, device 400 is fluid-based actuated.I.e., while a subject drinks a fluid (e.g., juice, water, etc.) 355through device 400.

Fluid 355 is supplied from a fluid reservoir 350 (e.g., a bottle, a can,etc.) to mouthpiece 320, which is fluidly connected to fluid reservoir350 by means of tubule 360.

While a subject (e.g., user, patient, etc.) drinks fluid 355, the fluidflows in tubule 360. Such flow creates pressure within said tubule.

Said pressure in tubule 360 actuates a trigger mechanism 337 inactuation point 359, such that the actuated trigger mechanism 337 opensvalve 335 to a predetermined period of time.

The result of that is the following: a predetermined amount of substance332 is released from container 330 to nosepiece 340 when said pressureis greater than a predetermined pressure threshold.

The pressure threshold is the minimum pressure needed to activatetrigger mechanism 337 and is in the range of about 0.1 Pascal to about30 Pascal.

According to some embodiments, trigger mechanism 337 is synchronizedwith the drinking of fluid 355 by the subject. According to thepreferred embodiment of the invention, fluid 355 which is drunk by thesubject activates the swallowing reflex that closes the soft palate fora specific period of time, such that the nasal passageways of saidsubject's nose are substantially isolated from the remainder of thepulmonary system. At this specific period of time, the substance isreleased from the device to the nasal passageways. According to someembodiments, the release of said substance is simultaneous with thedrinking and swallowing of said fluid.

According to some embodiments, trigger mechanism 337 is incorporatedwithin valve 335, such that there is one valve which is responsive to anexternal pressure of fluid and is responsible for releasing thesubstance to the nosepiece.

According to some embodiments, the actuation of the valve by the triggermechanism is at least partially based on the Venturi effect. This effectis based on the Bernoulli equation which states that the sum of allforms of energy in a gas flowing along an enclosed path is the same atany two points in that path (or streamline). Its formulation in thesimple hypothesis of incompressible flow (gas motion with negligiblechanges in density) is:

${\frac{v^{2}}{2} + {gh} + \frac{p}{\rho}} = {{const}.}$where: v is the gas velocity along the streamline, g is the accelerationof gravity on Earth, h is the height, p is the pressure along thestreamline, and ρ is the gas density. As a consequence of Bernoulli'slaw, a gas passing through smoothly varying constrictions is subjectedto changes in velocity and pressure. A Venturi is a system for speedingthe flow of the gas, by constricting it in a cone shaped tube. In therestriction, the fluid must increase its velocity, reducing its pressureand producing a vacuum. As the gas leaves the constriction, its pressureincreases back to the ambient or pipe level.

The opening of valve 335 is also influenced by the amount of substancewhich is released and the inspiratory force with which the subject isdrinking the fluid. According to the Venturi effect, the amount ofsubstance and the inspiratory force, or at least part of them, createthe predetermined pressure threshold mentioned above.

In order to reconfigure valve 335 to the active configuration, thepressure in tubule 360 has to be greater than this pressure threshold,such that trigger mechanism 337 is actuated and valve 335 is actuatedfor a predetermined period of time.

The drinking-actuated mechanism of the device of the present inventionhas the ability to eliminate bad flavor of the substance which isreleased into the subject's nose by combining the release of thesubstance in the nose with a “throat washing” effect by the fluid whichis simultaneously drunk by the subject. According to some embodiments ofthe invention, tubule 360 can be at least partially a straw.

According to the preferred embodiment of the invention, tubule 360 isfluidly connected to an external straw 362. According to someembodiments, straw 362 is insertable into fluid reservoir 350.

According to some embodiments of the invention, container 330 of device400 may comprise a piston 131 which is adapted to compress substance 332within the container 330. Such a compression creates pressure withincontainer 330 and pushes said substance 332 forward. In a preferredembodiment of the invention, piston 331 is located in the back side ofcontainer 130.

According to some embodiments, trigger mechanism 337 is adapted toreciprocally move piston 331 within container 330, when it is actuatedin response to the fluid 355 pressure within the tubule 360 while thesubject drinks the fluid.

According to some embodiment of the invention, trigger mechanism 337comprises a pulsation mechanism which is adapted to actuate valve 335 ina predetermined sequence of pulses.

Each pulse is characterized by a predetermined length of pulse (in time)in which a predetermined amount of said substance is released by saidvalve according to said sequence of pulses.

For example, the subject drinks the fluid so as to actuate the triggermechanism for a total amount of 4 seconds.

In this case, two doses of substance can be sprayed into the nose, thefirst dose between the first second and the second one, and the seconddose between the third second and the fourth second.

According to some embodiments, nosepiece 340 is in fluid communicationwith valve 335 by means of a spray nozzle. In this case, the spraynozzle might be a known in the art spray nozzle which is able to releasethe substance by spraying it into the nose. According to theseembodiments, the spray nozzle might be characterized by a diameter,which influences the predetermined period of time in which the substancereleased to the nose. According to some embodiments, container 330 is asyringe.

According to some embodiments, device 400 might comprise a cap which isadapted to cover at least a portion of the components of said device forsterilization/aseptic purposes. For example, a cap that covers thenosepiece, and/or the mouthpiece. This cap might comprise an opening.

According to one embodiment of the present invention, the device 400 isutilized for a single use (namely a disposable device). According toanother embodiment of the present invention, the device 400 is utilizedfor multiple uses.

According to a preferred embodiment of the invention, as illustrated inFIG. 11, device 400 might be mechanically connected (e.g., by piercingmeans) to external container 390. External container 390 is adapted tofill container 330 with substance 332.

According to some embodiments, external container 390 adapted to fillcontainer 330 with a predetermined and a specific dose of saidsubstance, for example, when the subject presses of the substancereleasing part of the external container.

According to another embodiment, the substance 332 is already providedwithin container 330.

According to some embodiments, device 400 might comprises indicatingmeans which are adapted to indicate the amount of substance within thecontainer.

According to some embodiments, the indicating means is a transparentwindow located on a side of the container.

According to some embodiments, the substance implemented by the deviceof the present invention may be a drug selected from a group consistingof: Anti-Angiogenesis agents, Antisense, anti-ulcer, butorphanol,Calcitonin and analogs, Cyclooxygenase (COX-II) inhibitors, desmopressinand analogs, dihydroergotamine, Dopamine agonists and antagonists,Enkephalins and other opioid peptides,

growth hormone and analogs, growth hormone releasing hormone, Growthhormone antagonists, IgE suppressors, Insulin, insulinotropin andanalogs, Ketamine, Kytril (granisetron), Leutenizing hormone releasinghormone and analogs, lidocaine, metoclopramide, Midazolam, Narcoticanalgesics, neuraminidase inhibitors, nicotine, Non-steroidanti-inflammatory agents, Oligosaccharides, ondansetron, Parathyroidhormone and analogs, Parathyroid hormone antagonists, Prostaglandinantagonists, Prostaglandins, Recombinant soluble receptors, scopolamine,Serotonin agonists and antagonists, Sildenafil, Terbutaline,vasopressin, or any combination thereof.

According to some embodiments, the substance implemented by the deviceof the present invention may be a vaccine with or without carriersand/or adjuvants selected from the group consisting of: Prophylacticsand therapeutic antigens, subunit protein, peptide and polysaccharide,polysaccharide conjugates, toxoids, genetic based vaccines, liveattenuated, reassortant, inactivated, whole cells, viral and bacterialvectors for the treatment of arthritis, Lactobacillus species:Lactobacillus acetotolerans, Lactobacillus acidifarinae, Lactobacillusacidipiscis, Lactobacillus acidophilus (Doderlein bacillus),Lactobacillus agilis, Lactobacillus algidus, Lactobacillus alimentarius,Lactobacillus amylolyticus, Lactobacillus amylophilus, Lactobacillusamylotrophicus, Lactobacillus amylovorus, Lactobacillus animalis,Lactobacillus antri, Lactobacillus apodemi, Lactobacillus aviarius,Lactobacillus bifermentans, Lactobacillus brevis, Lactobacillusbuchneri, Lactobacillus camelliae, Lactobacillus casei, Lactobacilluscatenaformis, Lactobacillus ceti, Lactobacillus coleohominis,Lactobacillus collinoides, Lactobacillus composti, Lactobacillusconcavus, Lactobacillus coryniformis, Lactobacillus crispatus,Lactobacillus crustorum, Lactobacillus curvatus, Lactobacillusdelbrueckii, Lactobacillus delbrueckii subsp. Bulgaricus, Lactobacillusdelbrueckii subsp. Lactis, Lactobacillus diolivorans, Lactobacillusequi, Lactobacillus equigenerosi, Lactobacillus farraginis,Lactobacillus farciminis, Lactobacillus fermentum, Lactobacillusfornicalis, Lactobacillus fructivorans, Lactobacillus frumenti,Lactobacillus fuchuensis, Lactobacillus gallinarum, Lactobacillusgasseri, Lactobacillus gastricus, Lactobacillus ghanensis, Lactobacillusgraminis, Lactobacillus hammesii, Lactobacillus hamsteri, Lactobacillusharbinensis, Lactobacillus hayakitensis, Lactobacillus helveticus,Lactobacillus hilgardii, Lactobacillus homohiochii, Lactobacillus iners,Lactobacillus ingluviei, Lactobacillus intestinalis, Lactobacillusjensenii, Lactobacillus johnsonii, Lactobacillus kalixensis,Lactobacillus kefiranofaciens, Lactobacillus kefiri, Lactobacilluskimchii, Lactobacillus kitasatonis, Lactobacillus kunkeei, Lactobacillusleichmannii, Lactobacillus lindneri, Lactobacillus malefermentans,Lactobacillus mali, Lactobacillus manihotivorans, Lactobacillusmindensis, Lactobacillus mucosae, Lactobacillus murinus, Lactobacillusnagelii, Lactobacillus namurensis, Lactobacillus nantensis,Lactobacillus oligofermentans, Lactobacillus oris, Lactobacillus panis,Lactobacillus pantheris, Lactobacillus parabrevis, Lactobacillusparabuchneri, Lactobacillus paracollinoides, Lactobacillusparafarraginis, Lactobacillus parakefiri, Lactobacillus paralimentarius,Lactobacillus paraplantarum, Lactobacillus pentosus, Lactobacillusperolens, Lactobacillus plantarum, Lactobacillus pontis, Lactobacilluspsittaci, Lactobacillus rennini, Lactobacillus reuteri, Lactobacillusrhamnosus, Lactobacillus rimae, Lactobacillus rogosae, Lactobacillusrossiae, Lactobacillus ruminis, Lactobacillus saerimneri, Lactobacillussakei, Lactobacillus salivarius, Lactobacillus sanfranciscensis,Lactobacillus satsumensis, Lactobacillus secaliphilus, Lactobacillussharpeae, Lactobacillus siliginis, Lactobacillus spicheri, Lactobacillussuebicus, Lactobacillus thailandensis, Lactobacillus ultunensis,Lactobacillus vaccinostercus, Lactobacillus vaginalis, Lactobacillusversmoldensis, Lactobacillus vini, Lactobacillus vitulinus,Lactobacillus zeae, Lactobacillus zymae, Probiotics selected from agroup consisting of Lactic acid bacteria (LAB) and bifidobacteria or anycombination thereof; said substance is used for the treatment of atleast one selected from a group consisting of cholera, moraxellacatarrhali, cocaine addiction, Haemophilus influenzae type b (Hib),meningococcus, measles, mumps, rubella, varicella, yellow fever,Respiratory syncytial virus, pneumococcus, streptococcus, typhoid,influenza, hepatitis, including hepatitis A, B, C and F, polio, humanimmunodeficiency virus (HIV), parainfluenza, rotavirus, cytomegalovirus(CMV), chlamydia, non-typeable haemophilus, moraxella catarrhalis, humanpapilloma virus, tuberculosis including Bacillus Calmette-Guerin (BCG),gonorrhoea, asthma, atheroschlerosis, malaria, otitis media, E-coli,Alzheimer's disease, H. Pylori, salmonella, diabetes, cancer, herpessimplex, Staphylococcus aureus, Streptococcus, or any combinationthereof.

According to some embodiments, the substance implemented by the deviceof the present invention is used for the treatment of at least oneselected from a group consisting of cholera, moraxella catarrhali,cocaine addiction, Hib, meningococcus, measles, mumps, rubella,varicella, yellow fever, Respiratory syncytial virus, pneumococcus,streptococcus, typhoid, influenza, hepatitis, including hepatitis A, B,C and F, polio, HIV, parainfluenza, rotavirus, CMV, chlamydia,non-typeable haemophilus, moraxella catarrhalis, human papilloma virus,tuberculosis including BCG, gonorrhoea, asthma, atheroschlerosis,malaria, otitis media, E-coli, Alzheimer's disease, H. Pylori,salmonella, diabetes, cancer, herpes simplex, Staphylococcus aureus,Streptococcus, or any combination thereof.

According to some embodiments, the substance is a peptide or proteintherapeutic agent such as cytokines, hormones, clotting factors,vaccines, monoclonal antibody.

According to some embodiments, the device is used for the treatment ofcentral nervous system (CNS) disorders, brain disorders such as: braincancer, acute brain injury, spinal cord injury, Alzheimer's disease,Neurogenesis, Parkinson's disease, depression, Epilepsy, schizophreniaby the delivery of substances such as: Neurotrophins, brain-derivedneurotrophic factor (BDNF), glial cell-derived neurotrophic factor(GDNF), anti-epidermal growth factor receptor antibodies (anti EGFreceptor AB), Enzymes such as Lysosomal enzyme, Neuregulin.

According to some embodiments, the substance implemented by the deviceof the present invention is selected from a group consisting of naturaloils; Mint oils, Peppermint oil, Spearmint oil, Menthol, Olive oil,Eucalyptus oil, Amino acids, fatty acids and any combination thereof.

According to some embodiments, the substance implemented by the deviceof the present invention may be a therapeutic substance selected from agroup consisting of: Agents for the common cold, Anti-addiction,anti-infectives, analgesics, anesthetics, anorexics, antiarthritics,anti-allergy agents, antiasthmatic agents, anticonvulsants,anti-depressants, antidiabetic agents, anti-depressants, anti-diuretics,anti-emetics, antihistamines, anti-inflammatory agents, antimigrainepreparations, antimotion sickness preparations, antinauseants,antineoplastics, anti-obesity, antiosteoporeteic, antiparkinsonismdrugs, antipruritics, antipsychotics, antipyretics, anticholinergics,benzodiazepine antagonists, bone stimulating agents, central nervoussystem stimulants, hormones, hypnotics, immunosuppressives,prostaglandins, proteins, peptides, polypeptides and othermacromolecules, psychostimulants, rhinitis treatment, sedatives, sexualhypofunction, tranquilizers and vitamins including B12, probiotics,natural oils, natural ingredients, or any combination thereof.

As mentioned above, the particle's or droplet's size has significantimpact on absorption when administering substance via the nose and thenasal epithelia. According to another embodiment of the presentinvention the particle's or droplet's size is in the micrometer andnanometer size.

The above disclosure is based on the user sucking (and drinking) liquid(e.g., water, juice etc.).

According to another embodiment of the present invention, the mechanismis based on the user inhaling air (instead of in taking fluid).Reference is now being made to FIG. 12 which generally illustrates theabove principle.

FIG. 12 illustrates the inhaling-actuating device 500 for delivering asubstance to a nasal cavity 501 of a subject. The device generallycomprises a mouthpiece 502 (through which the patient inhales and thusactivates the mechanism), a container 503 accommodating a medicament tobe delivered to said patient and a nose piece 504 adapted to dispensethe medicament to the nasal cavity of the patient.

Reference is now made to FIGS. 13-14 which generally illustrates thebasic concept behind the idea. FIG. 13 illustrates the mouth piece 502of the inhaling-actuating device 500 placed within the mouth of thepatient and the nose piece 504 placed within the nose of the patient.Under the heading Detailed Description of the Preferred Embodiments,page 30, paragraph 3 now reads:

FIG. 14 illustrates the inhaling-actuating device 500 once the same isactivated, namely, once the patient takes in (or sucks) air. As will bedescribed hereinafter, once the patient takes in air 505 theinhaling-actuating device 500 is activated and the medicament 506 isreleased to the nose 501 of the patient.

Reference is now being made to FIGS. 15-19 b, illustrating a firstspecific mechanism of the inhaling-actuating device 500 as describedabove.

FIG. 15 illustrates the inhaling-actuating device 500 prior to theactivation of the same (i.e., the air inhaling).

As can be seen in FIG. 15, the device comprises the nose piece 504 (tobe placed within the nasal cavity of the patient), the mouth piece 502(to be placed within the mouth of the patient, and a container 503 foraccommodating the medicament 506 to be delivered to the nasal cavity ofthe patient. The actuation mechanism (for activating the device anddelivering medicament to the patient's nasal cavity) comprises a firstunidirectional valve 507, a membrane 508, an intermediate compartment511 (for accommodating a uni-dose amount of medicament to be deliveredto the patient's nasal cavity), at least one spring 509 and a secondvalve means 510.

Prior to the actuation of device 500, the unidirectional valve 507enables filling of intermediate compartment 511 with the uni-dose amountof medicament 506. (As will be described hereinafter, this is enableddue to the fact that after said medicament is released to the nasalcavity, vacuum is created in said intermediate compartment 511, which‘draws’ said medicament 506 through unidirectional valve 507).

FIG. 16 a illustrates the device 500 in place in the nose and mouth ofthe patient. FIG. 16 b illustrates the activation of the device 500,namely, the sucking of air through mouth piece 502.

Reference is now being made to FIGS. 17-19 b, illustrating the actuationmechanism. Once the patient takes in air (through mouthpiece 502)membrane 508 is drawn downwardly (in the direction of container 503.Membrane 508 is in communication with said spring 509; such that, whenmembrane 508 is drawn downwardly, said spring 509 is loaded andcompressed.

Said spring 509 is in physical communication with valve means 510 suchthat, when spring 509 is loaded and compressed (as a result of thedownwards movement of the membrane 508) valve means 510 are opened andthe medicament 506 are released to the patient's nasal cavity.

It should be pointed out that valve means 510 additionally comprisessealing means 512 adapted to prevent the passage of medicament from theintermediate compartment 511 to the nasal cavity without the actuationof the patient (i.e., air suction).

Once the medicament is released to the nasal cavity, vacuum is createdin the intermediate compartment 511, which eventually enables thewithdrawal of another uni-dose amount of medicament 506 from thecontainer 503 through unidirectional valve 507.

Reference is now made to FIGS. 18 a-18 b and 19 a-19 b which provide acloser view of the actuation step of device 500. FIGS. 18 a-18 billustrates the device 500 prior to the actuation step and FIGS. 19 a-19b illustrates the device 500 post actuation.

As mentioned above, prior to the actuation, intermediate compartment 511is filled with a uni-dose amount of medicament. In this stage, the valvemeans 510 is closed and sealing means 512 seals said intermediatecompartment 511, preventing release of medicament to the patient.

FIGS. 19 a-19 b illustrates the device 500 post-actuation. As mentionedabove, once the patient takes in air, membrane 508 is actuated andwithdrawn downwardly such that spring 509 is loaded and compressed. Oncespring 509 is compressed, valve 510 is opened and the medicament isreleased from the intermediate compartment 511 to the nasal cavity.

Reference is now made to FIGS. 20-26 d which illustrate a secondembodiment 600 of the above mentioned concept.

According to this embodiment, there is a further step of ‘charging’ or‘loading’ the inhaling-actuating device 600 with the uni-dose amount ofmedicament 506.

Reference is now made to FIG. 20 which illustrates the main componentsof inhaling-actuating device 600, which comprises a mouthpiece 502, anosepiece 504, a unidirectional valve 507, a container 503 foraccommodating the medicament 506 and a loading mechanism 513.

Reference is now made to FIG. 21 and FIGS. 22 a-22 c which provides acloser view of the loading mechanism 513. As can be seen in FIGS. 22a-22 b, the loading mechanism 513 comprises a rotating knob 514, a firstactuator 515 and a second actuator 516, complementary to said firstactuator.

When the user wishes to load the device 600, he rotates knob 514 (seeFIG. 21). Said rotating knob comprises a spiral elevating means 518 incommunication with said first actuator 515. Rotation of the rotatingknob 514 rotates the spiral elevating means 518 which eventuallyelevates the first actuator 515 and pushes the same into thecomplementary second actuator 516.

The first actuator 515 is characterized by at least two wings 515 a and515 b, each of which comprises a protrusion (i.e., a bulge) 515 c-515 d,respectively.

Said complementary second actuator 516 comprises two grooves 516 a and516 b adapted to accommodate said bulge 515 c and 515 d.

Said complementary second actuator 516 is further coupled to a thirdcomplementary actuator 517. Said third complementary actuator 517comprises, like actuator 515, at least two wings 517 a and 517 b, eachof which comprises a protrusion (i.e., a bulge) 517 c and 517 d (517 dis not shown), respectively.

Once said rotating knob 514 is rotated and the first actuator iselevated into the complementary second actuator 516 and into the thirdcomplementary actuator 517; bulges 515 c and 515 d are positioned insidegrooves 516 a-516 b of the second actuator 516. Bulges 515 c and 515 dare held in place by bulges 517 c and 517 d of the third complementaryactuator 517 (see FIGS. 22 a-22 b).

Such movement of said actuator creates vacuum inside the intermediatecompartment 511, and thus, the device 600 is loaded with the dose to bedelivered to the patient (see FIG. 22 c).

Reference is now made to FIGS. 23-25 which illustrate-s the activationof device 600 (namely, air intake by the user, as seen in FIG. 25). Whenthe user takes in air, the medicament 506 is released to the user andmembrane 508 is elevated upward. Said membrane is coupled to said thirdcomplementary actuator 517.

Once said membrane 508 is elevated, said third complementary actuator517 is elevated as well. Said elevation pushes said wings 517 a and 517b inward so as to release said wings 515 a and 516 b of actuator 515.And thus, to return actuator 515 to its initial potion (the pre-loadingposition).

Reference is now made to FIGS. 26 a-26 d closely illustrating thedischarge of the actuator 515 to its initial potion. FIG. 26 aillustrates the actuator 515 (namely the bulge 515 d) coupled the thirdcomplementary actuator 517 (namely to bulge 517 d). Once the membrane508 is elevated (the user takes in air), the third complementaryactuator 517 is elevated, thus freeing said bulge 515 d of actuator 515from bulge 517 d of the third complementary actuator 517 (see FIG. 26b-26 d).

As mentioned above, the main difference between the first embodiment(device 500 illustrated in FIG. 12-19) and the second embodiment (device600 illustrated in FIG. 20-26 d) is the fact that the device of thefirst embodiment is reloaded automatically (i.e., once the medicament isreleased from the intermediate compartment 511, vacuum is created in thesame and another dose of medicament is withdrawn to said intermediatecompartment 511) and in the seconds embodiment, the loading is manual(i.e., the patient is required to actively load the device 500).

It should be made clear that simultaneously with the movement of 517 andthe return of 515 to its initial position, medicament 506 is released tothe patient.

Reference is now made to FIG. 26 e which illustrates the same. Once, themembrane 508 is activated, valve 510 is opened and the medicament 506 isreleased to the nasal cavity.

Reference is now made to FIGS. 27-28 illustrating another embodiment ofthe present invention, in which both the above mentioned mechanisms areactuated not by in taking (inhaling) air by the user. According to FIGS.27-28, the medicament dispensing is actuated by the pressing (i.e.,application of force) on a spring-like surface 520 which is inmechanical communication with membrane 508 and actuates the same.

Such a feature is highly important since, unlike the previous mechanisms(based on the intake of air by the patient, i.e., a subjective feature),this mechanism is based on a press of a button (an objective feature).For example, a relatively ill and weak patient may not have enoughstrength to inhale the required amount of air so as to activate themechanism or to take in the required amount of the uni-dose medicament.Such a mechanism eliminates such a problem.

Reference is now made to FIGS. 29-38 illustrating a third mechanismbased on the intake of air.

According to the third embodiment the inhaling-actuating device 700comprises a mouthpiece 502, a nosepiece 504 and an actuator 531 rotatedaround a hinge 530 (see FIG. 29).

FIG. 30 illustrates a cross sectional view of the same. In the figure,is can be seen that the hinge 530, around which said actuator 531 isrotated, is mechanically coupled to a spring 532 by means of a connector533. Said spring 532 is maintained retracted (i.e., loaded) by means ofa casing 534 (as will be disclosed hereinafter). Said inhaling-actuatingdevice 700 further comprises a container for containing a medicament 506(not shown).

Reference is now made to FIGS. 31-35, illustrating the actuation ofdevice 700.

FIG. 31 illustrates device 700 prior to the actuation. FIG. 32illustrates the first step of the actuation in which actuator 531 isrotated around hinge 530. Said rotation engages spring 532 and loads thesame (i.e., compresses the same). A second spring 535, encased within acasing 536, is linearly moved along a path which is substantiallyperpendicular to the main longitudinal axis of spring 532 and casing534. Under the heading Detailed Description of the PreferredEmbodiments, page 33, paragraph 2 now reads:

Casing 534 of spring 532 is characterized by at least one groove 537into which at least a portion of casing 536 of spring 535 is inserted soas to maintain spring 532 loaded.

As mentioned, said movement of said spring 535 and casing 536 engageswith the casing 534 of spring 532 (namely inserted into groove 537) soas to load (compress) spring 532.

FIGS. 33-34 illustrate the next step, in which medicament 506 is loadedinto device 700.

FIG. 35 illustrates the final step in which the device 700 is actuated.

As described above, the activation in initiated by the intake of air bythe user. Once the user inhales (see arrows 538) a membrane 508 (whichis mechanically coupled to spring 535) is withdrawn from spring 532.Said movement of said membrane withdraws also said spring 535 and casing536 (from groove 537 of spring 532).

Said withdrawal unloads spring 532 and the same is retracted to theinitial position. Said retraction is characterized by a piston-likemovement. I.e., when spring 532 is retracted, the same appliescompression forces on container 503 so as to be ‘pushed’ out. Suchpushing extracts said medicament 506 and the same is delivered to thenasal cavity of the patient (see arrow 540).

Reference is now made to FIGS. 36-37 which better illustrates theloading stage of the medicament 506 into device 700. Such loading isenabled due to the fact that the top part 550 of device 700 isreversibly coupled to the same.

When spring 502 is loaded (i.e., casing 536 is at least partially withingroove 537 of casing 534), the top part 550 of device 700 is de-coupledfrom device 700 and medicament 506 can be inserted into the same. FIG.37 illustrates a closer view of the medicament loading.

Reference is now made to FIGS. 38 a-38 b illustrating the top part 550prior to and post loading. As seen in FIG. 38 a container 503(containing the medicament 506) is inserted into the complementary toppart (sized and shape so as to accommodate the same) 550. FIG. 38 billustrates the top part 550 containing said container 503 containingsaid medicament 506.

Reference is now made to FIGS. 39-41, illustrating a fourth embodimentof the inhaling-actuating device 800. According to this embodiment, thedevice 800 comprises a container 503 containing a medicament 506 to bedelivered to the nasal cavity, a unidirectional valve 560, anintermediate container 511, a second unidirectional valve 561 and amembrane 508.

Prior to the actuation of the device 800 the intermediate container 511is filled with a uni-dose amount of medicament 506 (this is enabled dueto the fact that once the medicament is released to the nasal cavity,vacuum is generated within the intermediate container 511; thus,medicament is withdrawn into the same through unidirectional valve 561).

Once the patient takes in air (see FIG. 40), device 800 is actuated.Reference is now made to FIG. 40 illustrating the actuation mechanism.

Once the user inhales air (see arrows 562), membrane 508 is elevated.Membrane 508 is mechanically coupled to said valve 560, such that whensaid membrane 508 is elevated, valve 560 is elevated as well.

The elevation of valve 560 is characterized by a piston-like movement.I.e., when valve 560 is elevated, the same applies pressure on valve561, such that the medicament 506, contained within intermediatecontainer 511 is now released from the same into the nasal cavity (seearrows 564).

It should be pointed out that it is within the core concept of thepresent invention in which the nosepiece 504 can be designed andconfigured to be shaped for either one or two nostrils.

In the foregoing description, embodiments of the invention, includingpreferred embodiments, have been presented for the purpose ofillustration and description. They are not intended to be exhaustive orto limit the invention to the precise form disclosed. Obviousmodifications or variations are possible in light of the aboveteachings. The embodiments were chosen and described to provide the bestillustration of the principals of the invention and its practicalapplication, and to enable one of ordinary skill in the art to utilizethe invention in various embodiments and with various modifications asare suited to the particular use contemplated. All such modificationsand variations are within the scope of the invention as determined bythe appended claims when interpreted in accordance with the breadth theyare fairly, legally, and equitably entitled.

The invention claimed is:
 1. A drinking-actuated device configured fordelivering a substance to a nasal cavity of a subject, said devicecomprising: a. a container for containing said substance; b. a nosepieceextending from said device for placement in proximity to a nose of saidsubject, said nosepiece being in fluid communication with saidcontainer; c. a valve mechanically connectable to said container,characterized by at least two configurations: (i) an activeconfiguration in which said valve enables delivery of predeterminedamount of said substance from said container to said nasal cavity viasaid nosepiece; and, (ii) an inactive configuration; d. a mouthpieceextending from said device for placement in a mouth of said subject;and, e. a trigger mechanism configured to reconfigure said valve fromsaid active configuration to said inactive configuration, and viceversa; wherein said mouthpiece is fluidly connectable by means of atubule to a fluid reservoir containing a fluid, said fluid reservoir isconfigured to supply said fluid to said mouth of said subject via saidmouthpiece; further wherein said trigger mechanism is configured toreconfigure said valve from said inactive configuration to said activeconfiguration for a predetermined period of time in response to apressure gradient generated by suction applied by said subject to saidtubule for drinking said fluid through said tubule.
 2. Thedrinking-actuated device according to claim 1, wherein said triggermechanism is configured to reconfigure said valve from said activeconfiguration to said inactive configuration when said pressure gradientis absent.
 3. The drinking-actuated device according to claim 1, whereinsaid trigger mechanism comprises a controlling member configured to movereciprocally in response to said pressure gradient; said controllingmember is characterized by having at least two configurations: (i) aclosed configuration in which said fluid is not provided to said subjectvia said tubule and said valve is in said inactive configuration; and,(ii) an opened configuration in which said subject drinks said fluidthrough said tubule and said valve is in said active configuration;further wherein in said closed configuration, said controlling member isconfigured to block the passage of said fluid from said fluid reservoirto said mouthpiece.
 4. The drinking-actuated device according to claim3, wherein said trigger mechanism further comprises a flexible membrane,said flexible membrane is configured to reconfigure its shape inresponse to said pressure gradient caused by said suction applied bysaid subject to said tubule, such that said controlling member isreconfigured from said closed configuration to said openedconfiguration, and vice versa.
 5. The drinking-actuated device accordingto claim 4, wherein at least one of the following is being held true (a)said controlling member is characterized by at least three portions: afirst end positioned at least partially within said tubule; a middleportion mechanically connected with said membrane; and, a second end incommunication with said valve; (b) said controlling member comprises afirst aperture fluidly communicating said flexible membrane and saidmouthpiece, said first aperture is configured to transfer said pressuregradient from said tubule to said flexible membrane, so as toreconfigure said flexible membrane such that said controlling member isreconfigured from said closed configuration to said openedconfiguration; (c) said controlling member comprises a second apertureconfigured to facilitate passage of said fluid through said controllingmember when said controlling member is in said opened configuration,said passage of said fluid within said second aperture is configured topreserve said controlling member in said opened configuration while saidfluid passes through said controlling member; and any combinationthereof.
 6. The drinking-actuated device according to claim 5, whereinat least one of the following is being held true (a) said first end ofsaid controlling member is substantially perpendicular to said tubuleand substantially vertically movable within said tubule; (b) in thereconfiguration of said controlling member from said closedconfiguration to said opened configuration, said first end is configuredto move within and with respect to said tubule; and any combinationthereof.
 7. The drinking-actuated device according to claim 1, whereinat least one of the following is being held true (a) said valve isreconfigurable from said inactive configuration to said activeconfiguration when said pressure gradient is above a predeterminedthreshold; (b) said valve comprises a spring which is at least partiallytensed in said inactive configuration, and at least partially releasedin said active configuration; (c) said valve comprises a spring which isat least partially released in said inactive configuration, and at leastpartially tensed in said active configuration; (d) said drinking of saidfluid by said subject is configured to cause the soft palate of saidsubject to be closed, so that the nasal passageways of the nose of saidsubject is substantially isolated from the remainder of the pulmonarysystem; (e) said tubule is at least partially a straw; and anycombination thereof.
 8. The drinking-actuated device according to claim1, further comprising a piston configured to compress said substancewithin said container; wherein said valve is configured to move saidpiston towards said substance when said valve is configured to saidactive configuration.
 9. The drinking-actuated device according to claim1, wherein the operation of said trigger mechanism is synchronized withsaid drinking of said fluid by said subject.
 10. The drinking-actuateddevice according to claim 1, wherein said trigger mechanism comprises apulsation mechanism configured to reconfigure said valve from saidinactive configuration to said active configuration and vice versa insequence of pulses, each of which is characterized by a predeterminedlength of pulse, said valve configured to release said predeterminedamount of said substance according to said sequence of pulses.
 11. Thedrinking-actuated device according to claim 1, wherein said nosepiece isin fluid communication with said valve by means of a spray nozzle;further wherein said spray nozzle is characterized by a diameter whichinfluences said predetermined period of time.
 12. The drinking-actuateddevice according to claim 1, further comprising a cap configured tocover at least a portion of the components of said device forsterilization purposes; wherein said cap comprises an opening.
 13. Thedrinking-actuated device according to claim 1, wherein said container isconfigured to be connected to an external container, said externalcontainer is configured to fill said container with said substance;wherein said external container configured to fill said container with apredetermined dose of said substance.
 14. The drinking-actuated deviceaccording to claim 1, further comprising indicating means configured toindicate the amount of said substance within said container; furtherwherein said indicating means is a transparent window located on a sideof said container.
 15. The drinking-actuated device according to claim1, wherein at least one of the following is being held true (a) saidfluid is selected from a group consisting of: water, a juice, a fluidmedication, a cold fluid, a warm fluid, and any combination thereof; (b)said substance is used for the treatment of at least one selected from agroup consisting of cholera, moraxella catarrhali, cocaine addiction,Haemophilus influenzae type b (Hib), meningococcus, measles, mumps,rubella, varicella, yellow fever, Respiratory syncytial virus,pneumococcus, streptococcus, typhoid, influenza, hepatitis, includinghepatitis A, B, C and F, polio, human immunodeficiency virus (HIV),parainfluenza, rotavirus, cytomegalovirus (CMV), chlamydia, non-typeablehaemophilus, moraxella catarrhalis, human papilloma virus, tuberculosisincluding Bacillus Calmette-Guerin (BCG), gonorrhoea, asthma,atherosclerosis, malaria, otitis media, E-coli, H. Pylori, salmonella,diabetes, cancer and herpes simplex, Staphylococcus aureus,Streptococcus, central nervous system (CNS) disorders, brain disorderssuch as: brain cancer, acute brain injury, spinal cord injury,Alzheimer's disease, Neurogenesis, Parkinson's disease, depression,Epilepsy, schizophrenia by the delivery of substances such as:Neurotrophins, brain-derived neurotrophic factor (BDNF), glialcell-derived neurotrophic factor (GDNF), anti-epidermal growth factorreceptor antibodies (anti EGF receptor AB), Enzymes such as Lysosomalenzyme, Neuregulin; and any combination thereof; (c) said substance maybe delivered to said nasal cavity in a form selected from a groupconsisting of: a powder; a granule; a cachet; a capsule; a tablet; apaste; a cream; a gel; an ointment; a salve; a foam; a paste; a lotion;a cream; an oil suspension; a suspension; a solution; an emulsion; apatch; a stick; a spray, preferably a nasal spray, or a buccal spray; amouth wash; an aerosol from a Venturi effect; a drink; and anycombination thereof.
 16. The drinking-actuated device according to claim1, wherein said substance is a drug selected from a group consisting of:Anti-Angiogenesis agents, Antisense, anti-ulcer, butorphanol, Calcitoninand analogs, COX-II inhibitors, desmopressin and analogs,dihydroergotamine, Dopamine agonists and antagonists, Enkephalins andother opioid peptides, Growth hormone and analogs, growth hormonereleasing hormone, Growth hormone antagonists, Immunoglobulin E (IgE)suppressors, Insulin, insulinotropin and analogs, Ketamine, Kytril,Leutenizing hormone releasing hormone and analogs, lidocaine,metoclopramide, Midazolam, Narcotic analgesics, neuraminidaseinhibitors, nicotine, Non-steroid anti-inflammatory agents,Oligosaccharides, ondansetron, Parathyroid hormone and analogs,Parathyroid hormone antagonists, Prostaglandin antagonists,Prostaglandins, Recombinant soluble receptors, scopolamine, Serotoninagonists and antagonists, Sildenafil, Terbutaline, vasopressin, vaccinewith or without carriers and/or adjuvant selected from a groupconsisting of: Prophylactics and therapeutic antigens, subunit protein,peptide and polysaccharide, polysaccharide conjugates, toxoids, geneticbased vaccines, live attenuated, reassortant, inactivated, whole cells,viral and bacterial—vectors for the treatment of arthritis,Lactobacillus species: Lactobacillus acetotolerans, Lactobacillusacidifarinae, Lactobacillus acidipiscis, Lactobacillus acidophilus(Doderlein bacillus), Lactobacillus agilis, Lactobacillus algidus,Lactobacillus alimentarius, Lactobacillus amylolyticus, Lactobacillusamylophilus, Lactobacillus amylotrophicus, Lactobacillus amylovorus,Lactobacillus animalis, Lactobacillus antri, Lactobacillus apodemi,Lactobacillus aviarius, Lactobacillus bifermentans, Lactobacillusbrevis, Lactobacillus buchneri, Lactobacillus camelliae, Lactobacilluscasei, Lactobacillus catenaformis, Lactobacillus ceti, Lactobacilluscoleohominis, Lactobacillus collinoides, Lactobacillus composti,Lactobacillus concavus, Lactobacillus coryniformis, Lactobacilluscrispatus, Lactobacillus crustorum, Lactobacillus curvatus,Lactobacillus delbrueckii, Lactobacillus delbrueckii subsp. Bulgaricus,Lactobacillus delbrueckii subsp. Lactis, Lactobacillus diolivorans,Lactobacillus equi, Lactobacillus equigenerosi, Lactobacillusfarraginis, Lactobacillus farciminis, Lactobacillus fermentum,Lactobacillus fornicalis, Lactobacillus fructivorans, Lactobacillusfrumenti, Lactobacillus fuchuensis, Lactobacillus gallinarum,Lactobacillus gasseri, Lactobacillus gastricus, Lactobacillus ghanensis,Lactobacillus graminis, Lactobacillus hammesii, Lactobacillus hamsteri,Lactobacillus harbinensis, Lactobacillus hayakitensis, Lactobacillushelveticus, Lactobacillus hilgardii, Lactobacillus homohiochii,Lactobacillus iners, Lactobacillus ingluviei, Lactobacillusintestinalis, Lactobacillus jensenii, Lactobacillus johnsonii,Lactobacillus kalixensis, Lactobacillus kefiranofaciens, Lactobacilluskefiri, Lactobacillus kimchii, Lactobacillus kitasatonis, Lactobacilluskunkeei, Lactobacillus leichmannii, Lactobacillus lindneri,Lactobacillus malefermentans, Lactobacillus mali, Lactobacillusmanihotivorans, Lactobacillus mindensis, Lactobacillus mucosae,Lactobacillus murinus, Lactobacillus nagelii, Lactobacillus namurensis,Lactobacillus nantensis, Lactobacillus oligofermentans, Lactobacillusoris, Lactobacillus panis, Lactobacillus pantheris, Lactobacillusparabrevis, Lactobacillus parabuchneri, Lactobacillus paracollinoides,Lactobacillus parafarraginis, Lactobacillus parakefiri, Lactobacillusparalimentarius, Lactobacillus paraplantarum, Lactobacillus pentosus,Lactobacillus perolens, Lactobacillus plantarum, Lactobacillus pontis,Lactobacillus psittaci, Lactobacillus rennini, Lactobacillus reuteri,Lactobacillus rhamnosus, Lactobacillus rimae, Lactobacillus rogosae,Lactobacillus rossiae, Lactobacillus ruminis, Lactobacillus saerimneri,Lactobacillus sakei, Lactobacillus salivarius, Lactobacillussanfranciscensis, Lactobacillus satsumensis, Lactobacillus secaliphilus,Lactobacillus sharpeae, Lactobacillus siliginis, Lactobacillus spicheri,Lactobacillus suebicus, Lactobacillus thailandensis, Lactobacillusultunensis, Lactobacillus vaccinostercus, Lactobacillus vaginalis,Lactobacillus versmoldensis, Lactobacillus vini, Lactobacillusvitulinus, Lactobacillus zeae, Lactobacillus zymae, Probiotics selectedfrom a group consisting of Lactic acid bacteria (LAB) andbifidobacteria, and any combination thereof; a therapeutic substanceselected from a group consisting of: Agents for the common cold,Anti-addiction, anti-infectives, analgesics, anesthetics, anorexics,antiarthritics, anti-allergy agents, antiasthmatic agents,anticonvulsants, anti-depressants, antidiabetic agents,anti-depressants, anti-diuretics, anti-emetics, antihistamines,anti-inflammatory agents, antimigraine preparations, antimotion sicknesspreparations, antinauseants, antineoplastics, anti-obesity,antiosteoporeteic, antiparkinsonism drugs, antipruritics,antipsychotics, antipyretics, anticholinergics, benzodiazepineantagonists, bone stimulating agents, central nervous system stimulants,hormones, hypnotics, immunosuppressives, prostaglandins, proteins,peptides, polypeptides and other macromolecules, psychostimulants,rhinitis treatment, sedatives, sexual hypofunction, tranquilizers andvitamins including B12, probiotics, natural oils, natural ingredients,peptide or protein therapeutic agent such as cytokines, hormones,clotting factors, vaccines, monoclonal antibody, natural oils; Mintoils, Peppermint oil, Spearmint oil, Menthol, Olive oil, Eucalyptus oil,Amino acids, fatty acids and any combination thereof.
 17. A method fordelivering a substance to a nasal cavity of a subject, said methodcomprising steps of: a. providing a drinking-actuated device configuredfor delivering a substance to a nasal cavity of a subject, said devicecomprising: (i) a container for containing said substance; (ii) anosepiece extending from said device for placement in proximity to anose of said subject, said nosepiece being in fluid communication withsaid container; (iii) a valve mechanically connectable to saidcontainer, characterized by at least two configurations: (i) an activeconfiguration in which said valve causes a delivery of predeterminedamount of said substance from said container to said nasal cavity viasaid nosepiece; and (ii) an inactive configuration in which saidsubstance is not delivered to the nose of said subject; (iv) amouthpiece extending from said device for placement in a mouth of saidsubject; and, a trigger mechanism configured to reconfigure said valvefrom said active configuration on to said inactive configuration, andvice versa; (v) wherein said mouthpiece is fluidly connectable by meansof a tubule to a fluid reservoir containing a fluid, said fluidreservoir is configured to supply said fluid to said mouth of saidsubject via said mouthpiece; b. placing said nosepiece in or around thenose of said subject; c. fluidly connecting said tubule to said fluidreservoir; d. placing said mouthpiece in the mouth of said subject; e.drinking said fluid through said mouthpiece, thereby reconfiguring saidvalve via said trigger mechanism from said inactive configuration tosaid active configuration for a predetermined period of time in responseto a pressure gradient generated by suction applied to said tubule whilesaid subject drinks said fluid through said tubule; f. releasing saidpredetermined amount of said substance from said container to saidnosepiece wherein in a closed configuration, a controlling member isconfigured to block the passage of said fluid from said fluid reservoirto said mouthpiece.
 18. The method for delivering a substance to a nasalcavity of a subject according to claim 17, further comprising at leastone step selected from a group consisting of (a) reconfiguring saidvalve via said trigger mechanism from said active configuration to saidinactive configuration when said pressure gradient is absent; (b)providing said trigger mechanism with said controlling member configuredto move reciprocally within said tubule and said valve in responsive tosaid pressure gradient; said controlling member is characterized byhaving at least two configurations: (i) said closed configuration inwhich said fluid is not provided to said subject via said tubule andsaid valve is in said inactive configuration; and, (ii) an openedconfiguration in which said subject drinks said fluid through saidtubule and said valve is in said active configuration; and anycombination thereof.
 19. The method for delivering a substance to anasal cavity of a subject according to claim 17, further comprisingsteps of: providing said trigger mechanism with a flexible membrane;reconfiguring the shape of said flexible membrane in response to saidpressure gradient; and, thereby reconfiguring said controlling member isfrom said closed configuration to said opened configuration, and viceversa.
 20. The method for delivering a substance to a nasal cavity of asubject according to claim 19, wherein at least one of the following isbeing held true (a) said controlling member is characterized by at leastthree portions: a first end positioned at least partially within saidtubule; a middle portion mechanically connected with said membrane; and,a second end in communication with said valve; (b) said method furthercomprising steps of providing said controlling member with a firstaperture fluidly communicating between said membrane and saidmouthpiece, transferring said pressure gradient from said tubule to saidflexible membrane, thereby reconfiguring said controlling member fromsaid opened configuration to said closed configuration; (c) said methodfurther comprising steps of providing said controlling member with asecond aperture configured to facilitate passage of said fluid throughsaid controlling member when said controlling member is in said openedconfiguration, said passage of said fluid within said second aperture isconfigured to preserve said controlling member in said openedconfiguration while said fluid passes through said controlling member;and any combination thereof.
 21. The method for delivering a substanceto a nasal cavity of a subject according to claim 17, further comprisingat least one step selected from a group consisting of (a) reconfiguringsaid valve from said inactive configuration to said active configurationwhen said pressure gradient is above a predetermined threshold; (b)providing said valve with a spring which is at least partially tensed insaid inactive configuration, and at least partially released in saidactive configuration; (c) providing said valve with a spring which is atleast partially released in said inactive configuration, and at leastpartially tensed in said active configuration; (d) closing the softpalate of said subject as a result of said step (f) of drinking saidfluid, and thereby substantially isolating the nasal passageways of thenose of said subject from the pulmonary system; (e) compressing saidsubstance within said container via a piston; (f) providing said triggermechanism with a pulsation mechanism configured to reconfigure saidvalve from said inactive configuration to said active configuration andvice versa in sequence of pulses, each of which is characterized by apredetermined length of pulse, said valve configured to release saidpredetermined amount of said substance according to said sequence ofpulses; and any combination thereof.
 22. The method for delivering asubstance to a nasal cavity of a subject according to claim 17, whereinat least one of the following is being held true (a) said tubule is atleast partially a straw; (b) said fluid is selected from a groupconsisting of: water, juice, a fluid medication, a cold fluid, a warmfluid, and any combination thereof.
 23. The method for delivering asubstance to a nasal cavity of a subject according to claim 17, furthercomprising step of synchronizing operation of said trigger mechanismwith said drinking of said fluid by said subject.
 24. The method fordelivering a substance to a nasal cavity of a subject according to claim17, further comprising a step of providing said device with a capconfigured to cover at least a portion of the components of said devicefor sterilization purposes; wherein said cap comprises an opening. 25.The method for delivering a substance to a nasal cavity of a subjectaccording to claim 17, wherein said container is configured to beconnected to an external container, said external container configuredto fill said container with said substance; further comprising a step offilling said container by said external container with a predetermineddose of said substance.
 26. The method for delivering a substance to anasal cavity of a subject according to claim 17, further comprising astep of providing said container with indicating means configured toindicate the amount of said substance within said container; whereinsaid indicating means is a transparent window located on a side of saidcontainer.
 27. The method for delivering a substance to a nasal cavityof a subject according to claim 17, additionally comprising a step ofselecting said substance from a group consisting of a drug selected froma group consisting of: Anti-Angiogenesis agents, Antisense, anti-ulcer,butorphanol, Calcitonin and analogs, COX-II inhibitors, desmopressin andanalogs, dihydroergotamine, Dopamine agonists and antagonists,Enkephalins and other opioid peptides, Growth hormone and analogs,growth hormone releasing hormone, Growth hormone antagonists, IgEsuppressors, Insulin, insulinotropin and analogs, Ketamine, Kytril,Leutenizing hormone releasing hormone and analogs, lidocaine,metoclopramide, Midazolam, Narcotic analgesics, neuraminidaseinhibitors, nicotine, Non-steroid anti-inflammatory agents,Oligosaccharides, ondansetron, Parathyroid hormone and analogs,Parathyroid hormone antagonists, Prostaglandin antagonists,Prostaglandins, Recombinant soluble receptors, scopolamine, Serotoninagonists and antagonists, Sildenafil, Terbutaline, vasopressin, avaccine with or without carriers and/or adjuvant selected from the groupconsisting of: Prophylactics and therapeutic antigens, subunit protein,peptide and polysaccharide, polysaccharide conjugates, toxoids, geneticbased vaccines, live attenuated, reassortant, inactivated, whole cells,viral and bacterial vectors for the treatment of arthritis,Lactobacillus species: Lactobacillus acetotolerans, Lactobacillusacidifarinae, Lactobacillus acidipiscis, Lactobacillus acidophilus(Doderlein bacillus), Lactobacillus agilis, Lactobacillus algidus,Lactobacillus alimentarius, Lactobacillus amylolyticus, Lactobacillusamylophilus, Lactobacillus amylotrophicus, Lactobacillus amylovorus,Lactobacillus animalis, Lactobacillus antri, Lactobacillus apodemi,Lactobacillus aviarius, Lactobacillus bifermentans, Lactobacillusbrevis, Lactobacillus buchneri, Lactobacillus camelliae, Lactobacilluscasei, Lactobacillus catenaformis, Lactobacillus ceti, Lactobacilluscoleohominis, Lactobacillus collinoides, Lactobacillus composti,Lactobacillus concavus, Lactobacillus coryniformis, Lactobacilluscrispatus, Lactobacillus crustorum, Lactobacillus curvatus,Lactobacillus delbrueckii, Lactobacillus delbrueckii subsp. Bulgaricus,Lactobacillus delbrueckii subsp. Lactis, Lactobacillus diolivorans,Lactobacillus equi, Lactobacillus equigenerosi, Lactobacillusfarraginis, Lactobacillus farciminis, Lactobacillus fermentum,Lactobacillus fornicalis, Lactobacillus fructivorans, Lactobacillusfrumenti, Lactobacillus fuchuensis, Lactobacillus gallinarum,Lactobacillus gasseri, Lactobacillus gastricus, Lactobacillus ghanensis,Lactobacillus graminis, Lactobacillus hammesii, Lactobacillus hamsteri,Lactobacillus harbinensis, Lactobacillus hayakitensis, Lactobacillushelveticus, Lactobacillus hilgardii, Lactobacillus homohiochii,Lactobacillus iners, Lactobacillus ingluviei, Lactobacillusintestinalis, Lactobacillus jensenii, Lactobacillus johnsonii,Lactobacillus kalixensis, Lactobacillus kefiranofaciens, Lactobacilluskefiri, Lactobacillus kimchii, Lactobacillus kitasatonis, Lactobacilluskunkeei, Lactobacillus leichmannii, Lactobacillus lindneri,Lactobacillus malefermentans, Lactobacillus mali, Lactobacillusmanihotivorans, Lactobacillus mindensis, Lactobacillus mucosae,Lactobacillus murinus, Lactobacillus nagelii, Lactobacillus namurensis,Lactobacillus nantensis, Lactobacillus oligofermentans, Lactobacillusoris, Lactobacillus panis, Lactobacillus pantheris, Lactobacillusparabrevis, Lactobacillus parabuchneri, Lactobacillus paracollinoides,Lactobacillus parafarraginis, Lactobacillus parakefiri, Lactobacillusparalimentarius, Lactobacillus paraplantarum, Lactobacillus pentosus,Lactobacillus perolens, Lactobacillus plantarum, Lactobacillus pontis,Lactobacillus psittaci, Lactobacillus rennini, Lactobacillus reuteri,Lactobacillus rhamnosus, Lactobacillus rimae, Lactobacillus rogosae,Lactobacillus rossiae, Lactobacillus ruminis, Lactobacillus saerimneri,Lactobacillus sakei, Lactobacillus salivarius, Lactobacillussanfranciscensis, Lactobacillus satsumensis, Lactobacillus secaliphilus,Lactobacillus sharpeae, Lactobacillus siliginis, Lactobacillus spicheri,Lactobacillus suebicus, Lactobacillus thailandensis, Lactobacillusultunensis, Lactobacillus vaccinostercus, Lactobacillus vaginalis,Lactobacillus versmoldensis, Lactobacillus vini, Lactobacillusvitulinus, Lactobacillus zeae, Lactobacillus zymae, Probiotics selectedfrom a group consisting of Lactic acid bacteria (LAB) andbifidobacteria, or any combination thereof; said substance is used forthe treatment of at least one selected from a group consisting ofcholera, moraxella catarrhali, cocaine addiction, Hib, meningococcus,measles, mumps, rubella, varicella, yellow fever, Respiratory syncytialvirus, pneumococcus, streptococcus, typhoid, influenza, hepatitis,including hepatitis A, B, C and F, polio, HIV, parainfluenza, rotavirus,CMV, chlamydia, non-typeable haemophilus, moraxella catarrhalis, humanpapilloma virus, tuberculosis including BCG, gonorrhoea, asthma,atheroschlerosis, malaria, otitis media, E-coli, Alzheimers, H. Pylori,salmonella, diabetes, cancer and herpes simplex, Staphylococcus aureus,Streptococcus, a therapeutic substance selected from a group consistingof: Agents for the common cold, Anti-addiction, anti-infectives,analgesics, anesthetics, anorexics, antiarthritics, anti-allergy agents,antiasthmatic agents, anticonvulsants, anti-depressants, antidiabeticagents, anti-depressants, anti-diuretics, anti-emetics, antihistamines,anti-inflammatory agents, antimigraine preparations, antimotion sicknesspreparations, antinauseants, antineoplastics, anti-obesity,antiosteoporeteic, antiparkinsonism drugs, antipruritics,antipsychotics, antipyretics, anticholinergics, benzodiazepineantagonists, bone stimulating agents, central nervous system stimulants,hormones, hypnotics, immunosuppressives, prostaglandins, proteins,peptides, polypeptides and other macromolecules, psychostimulants,rhinitis treatment, sedatives, sexual hypofunction, tranquilizers andvitamins including B12, probiotics, natural oils, natural ingredients,peptide or protein therapeutic agent such as cytokines, hormones,clotting factors, vaccines, monoclonal antibody, natural oils; Mintoils, Peppermint oil, Spearmint oil, Menthol, Olive oil, Eucalyptus oil,Amino acids, fatty acids, or any combination thereof.
 28. The method fordelivering a substance to a nasal cavity of a subject according to claim17, wherein at least one of the following is being held true (a) saidsubstance is used for the treatment of at least one selected from agroup consisting of cholera, moraxella catarrhali, cocaine addiction,HIB, meningococcus, measles, mumps, rubella, varicella, yellow fever,Respiratory syncytial virus, pneumococcus, streptococcus, typhoid,influenza, hepatitis, including hepatitis A, B, C and F, polio, HIV,parainfluenza, rotavirus, CMV, chlamydia, non-typeable haemophilus,moraxella catarrhalis, human papilloma virus, tuberculosis includingBCG, gonorrhoea, asthma, atheroschlerosis, malaria, otitis media,E-coli, H. Pylori, salmonella, diabetes, cancer and herpes simplex,Staphylococcus aureus, Streptococcus, CNS disorder, brain disorders suchas: brain cancer, acute brain injury, spinal cord injury, Alzheimer'sdisease, Neurogenesis, Parkinson's disease, depression, Epilepsy,schizophrenia by the delivery of substances such as: Neurotrophins,BDNF, GDNF, anti EGF receptor AB, Enzymes as Lysosomal enzyme,Neuregulin or any combination thereof; (b) said substance may bedelivered to said nasal cavity in a form selected from the groupconsisting of: a powder; a granule; a cachet; a capsule; a tablet; apaste; a cream; a gel; an ointment; a salve; a foam; a paste; a lotion;a cream; an oil suspension; a spray; a suspension; a solution; anemulsion; a patch; a stick; a spray, preferably a nasal spray, or abuccal spray; a mouth wash; an aerosol, from a Venturi effect; a drink;and any combination thereof.